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SULFANILAMIDE AND ISATIN ANALOGUES AMONG THE NITROGEN HETEROCYCLES. PART 1. SULFANILYL DERIVATIVES OF PYRIDINE AND QUINOLINE-AMINES. PART II. THE SANDMEYER ISATIN SYNTHESIS APPLIED TO PYRIDINE AND QUINOLINE-AMINES

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.V/55
W interbottom, Robert.
S u l f a n i l a m i d e and i s a t i n a n a l o g u e s
among the n i t r o g e n h e t e r o c y c l e s . F a r t I .
S u l f a n i l y l d e r i v a t i v e s o f p y r i d i n e and
q u i n o l i n e a m i n e s . P a r t I I . The Sandmeycr
i s a t i n s y n t h e s i s a p p lie d to p y rid in e
and q u i n o l i n e amines. . .
Hew York,
1940.
5 p .l.,6 G ty p ew ritten leaves,
table,
diagrs.
29cm.
T h e s i s ( P h . D . ) - Hew York u n i v e r s i t y ,
Graduate sch o o l,
1940.
B ibliography
.'.27-23,65.
.
AS4435
Xerox University Microfilms,
Ann Arbor, Michigan 48106
T H IS D IS S E R T A T IO N HAS BEEN M IC R O F I L M E D E X A C T L Y AS R E C E IV E D .
L ib r a r y
Li. Y . I W
SULFANILAMIDE AND ISATIN ANALOGUES AMONG
THE NITROGEN HETEROCYCLES
PART I
S u l f a n i l y l D e r i v a t i v e s o f P y r i d i n e and Q u i n o l i n e Amines
PART I I
The Sandm eyer I s a t i n S y n t h e s i s A p p l i e d t o P y r i d i n e and
Q u i n o l i n e Amines
A T h e sis
S u b m itte d i n p a r t i a l f u l f i l l m e n t o f t h e
r e q u ir e m e n t s f o r t h e d e g r e e o f
D o cto r o f P h ilo so p h y
at
New York U n i v e r s i t y
by
R o b e r t W in t e r b o t to m
June 1 94 0
A ck n o w led g em en t
The a u t h o r a c k n o w le d g e s h i s a p p r e c i a t i o n
t o P r o f e s s o r H. G. L i n d w a l l f o r h i s k in d
a d v i c e and g u id a n c e t h r o u g h o u t t h e c o u r s e
of th is in v e s tig a tio n .
TABLE OF CONTENTS
TABLE OF CONTENTS
Part I
Page
C h ap ter I
The C h e m o t h e r a p e u t ic A c t i v i t y o f S u l f a n i l a m i d e s
i n R e l a t i o n t o t h e i r C h e m ic a l S t r u c t u r e
1
C h a p ter I I
D is c u s s io n o f E x p erim en ta l
A m in o p y r id in e s
9
A m in o q u in o lin e s
12
S u l f a n i l y l D e r i v a t i v e s o f A m in o p y r id in e s
and A m i n o q u i n o l i n e s
14
E x p erim en ta l
4 - A r a in o p y r id in e
16
5 - , 7 - , and 8 - A m i n o q u i n o l i n e
17
6 - A m i n o q u in o lin e
18
2 -S u lfa n ila m id o p y r id in e
20
5 -3 u lfa n ila m id o -2 -a m in o p y r id in e
21
3 -S u lfa n ila m id o p y r id in e
23
S u lfa n ila m id o q u in o lin e s
24
M e l t i n g P o i n t s and A n a l y t i c a l D a ta
26
B ib lio g r a p h y
27
P a r t II
C h a p ter I
In tro d u ctio n
29
Page
C h a p te r I I
D is c u s s io n o f E x p erim en ta l
(A) I s o n l t r o s o a c e t y l D e r i v a t i v e s
35
Iso n itr o so a c e ty la m in o p y r id in es
37
I so n itr o so a c e ty la m in o q u in o lin e s
39
(B ) R in g C lo s u r e t o I s a t i n S t r u c t u r e
39
(C ) R e a c t i o n s o f l , 2 - d i k e t o - 3 - p y r r o l o
£ 3 ,2 -f]
q u in o lin e
46
(D ) The S y n t h e s i s o f 4 , 7 - P h e n a n t h r o l i n e s
48
E x p erim en ta l
3 -Iso n itr o so a c e ty la m in o p y r id in e
52
5 -Iso n itr o so a c e ty la m in o q u in o lin e
53
6 -Iso n itr o so a c e ty la m in o q u in o lin e
54
1 , 2 - D ik e t o - 3 - p y r r o l o [ 3 ,2 -f] q u in o lin e
56
Oxime o f 1 , 2 - D i k e t o - 3 - p y r r o l o [ 3 , 2 - f ) q u i n o l i n e
58
B arium s a l t o f ( 6 - a m i n o - 5 - q u i n o l y l - )
g ly o x y lic a c id
59
3 -M e th y l-4 ,7 -p h e n a n th r o lin e -l-c a r b o x y lic a c id
60
3 -M e th y l-4 ,7 -p h e n a n th r o lin e
61
3 -P h e n y l-4 ,7 -p h e n a n th r o lin e -l-c a r b o x y lic a c id
62
l-C a r b o m e th o x y -3 -p h e n y l-4 ,7 -p h e n a n th r o lin e
63
3 -P h e n y l-4 ,7 -p h e n a n th r o lin e
64
B ib lio g r a p h y
65
Summary
66
PART I - CHAPTER I
-1 C h a p te r I - P a r t I
The C h e m o th e r a p e u t ic A c t i v i t y o f S u l f a n i l a m i d e s
i n R e l a t i o n t o t h e i r C h e m ic a l S t r u c t u r e
The i n c e p t i o n o f th e r e c e n t i n t e n s i v e s t u d y o f
s u lf a n ila m id e s by c h e m is ts , e x p e r im e n ta l p a t h o lo g is t s
and c l i n i c i a n s d a t e s from a p u b l i c a t i o n by Domagk^ in
1935.
A t t h a t t im e t h e r em a rk a b le c h e m o t h e r a p e u t i c
a c t i o n o f P r o n t o s i l i n th e t r e a t m e n t o f m ic e e x p e r i ­
m e n t a l l y i n f e c t e d w i t h h a e m o l y t i c s t r e p t o c o c c i was
announced.
S h o r tly a f t e r t h is d is c o v e r y , T refo u el
p
made th e
im p o r t a n t o b s e r v a t i o n t h a t a z o compounds w h ich d i d n o t
c o n t a i n a s u l f o n a m i d e g ro u p w ere i n a c t i v e .
T h is l e d
t o t h e c o n c l u s i o n t h a t i n v i v o th e a z o g r o u p in g was
r e d u c e d fo r m in g p -a m in o b e n z e n e s u l f o n a m i d e w h ic h was
th e e f f e c t i v e b a c t e r i c i d a l a g e n t .
v e s t i g a t i o n proved t h i s
E x p erim en ta l i n ­
t o be t r u e .
In s p i t e o f th e f a c t t h a t th e l i t e r a t u r e on
s u l f a n i l a m i d e s numbers o v e r 4 0 0 r e f e r e n c e s , a r e l a t i v e l y
fe w o u t s t a n d i n g p u b l i c a t i o n s sum m arize m o st o f t h e
-2
p u b l i s h e d work on new d e r i v a t i v e s .
3
Q
°
The c o n f u s i o n
a r i s i n g fr o m t h e a p p l i c a t i o n o f o r d i n a r y m eth ods o f
n o m e n c la t u r e t o t h e more co m p lex s u l f a n i l a m i d e d e r i v a t i v e 3 p rom p ted C r o s s l e y , H o r th e y and H u l t q u i s t
8
t o d e v i s e a new m ethod w h ic h was r e a d i l y a d o p t e d by
o t h e r w o r k e r s i n th e f i e l d .
"a) Naming a s s u b s t i t u t e d s u l f a n i l a m i d e s
SOgN1
JT
In s u l f a n i l a m i d e , t h e s u l f o n a m i d e group
b e i n g th e p r i n c i p a l f u n c t i o n a l g r o u p ,
o c c u p i e s t h e 1 - p o s i t i o n in t h e r i n g .
The n i t r o g e n a t o m s . a r e d i f f e r e n t i a t e d
by s u p e r s c r i p t s : N r e f e r r i n g t o s u b ­
s t i t u e n t s on t h e amide n i t r o g e n a n d N
t o s u b s t i t u e n t s on t h e amine n i t r o g e n .
The f o l l o w i n g e x a m p le s i l l u s t r a t e th e
m e th o d .
SOgNHCHg
S02NH2
\ >
CH3
NHCHg
NBg
N^-MethylSulfanilam ide
3-lfethylSulfanilam ide
N^-MethylSiolf a n il amide
b ) R a d i c a l Names - F o r s i m p l e d e r i v a t i v e s
t h e ab o v e m ethod s h o u ld be u s e d , b u t i t
b ecom es u n w i e l d y i n nam ing compounds w i t h
c o m p le x s u b s t i t u e n t s .
In s u c h c a s e s
r a d i c a l names a r e u s e f u l .
The f o l l o w i n g
r a d ic a ls are su g g ested :
W r
A
-NHg
S ulfanilyl
Metanilyl
Orthanilyl
T h e se names f o l l o w d i r e c t l y fr o m t h e
c o r r e s p o n d i n g amino a c i d s #
An ex a m p le
o f t h e i r u s e f u l n e s s i s shown by th e
compound
\
>*NHS02
S 0 2 NH
SOgH
S03H
w h ic h we name N jN ’ - d i s u l f a n i l y l b e n z i d i n e ^ ^ 1
d isu lfo n ic a c id .
A s i m p l e r c a s e i s an im p o r t a n t i n t e r m e d i a t e ,
w h ic h we c a l l
S0,C1
sK 2
V
NHCOCSj
N - a c e t y l s u l f a n i l y l c h lo r id e i n s t e a d of
p -a ceta m id o b en zen e s u l f o n y l c h l o r i d e .
O th er u s e f u l r a d i c a l s a re
OoNH-
NH-
SO2NH-
V
Sulfanilamido-
Metanilamido-
Orthanilamido-
-4 -
An ex a m p le I s
SQgH_
ty ~ (
>=53
,--------- x
w h ic h we name 2 , 4 - b i s - s u l f a n i l a m i d o t o l u e n e 5 - s u l f o n i c a c id ."
A r e v i e w o f th e e x i s t i n g l i t e r a t u r e a t t h e tim e
th is
r e s e a r c h was f o r m u l a t e d , show ed t h a t t h e r e was a
d e f i n i t e c o r r e l a t i o n b e tw e en t h e c h e m i c a l s t r u c t u r e
3 —8
o f s u l f a n i l a m i d e s and t h e i r c h e m i c a l c o n s t i t u t i o n .
The e v i d e n c e f o r th e b a c t e r i c i d a l p r o p e r t i e s o f some
compounds i s
somewhat i n c o n c l u s i v e , d i f f e r e n t w o r k e r s
p u b l i s h i n g r e s u l t s w h ich a r e c o n t r a d i c t o r y .
T h is i s
in p a r t due t o th e v a r i a t i o n i n t h e ty p e and s t r a i n
o f p a t h o g e n i c c o c c i e m p lo y e d and t o th e m e th o d s u s e d
in t h e i r ch em o th era p eu tic a s s a y .
a lte r a tio n
The e f f e c t s
i n th e p a r e n t s t r u c t u r e ,
of
su lfa n ila m id e ,
may be m ost r e a d i l y o r g a n i z e d by c o n s i d e r i n g
i n d i v i d u a l c h a n g e s in t h e tw o f u n c t i o n a l g r o u p s ,
a)
I n f l u e n c e o f t h e R e l a t i v e P o s i t i o n o f Amino and
S u lfo n a m id e G r o u p s.
S h i f t i n g th e amino group t o th e m eta o r o r t h o p o s i t i o n
r e s u l t s in compounds w h ic h a r e d e v o i d o f a c t i o n .
The
para r e l a t i o n s h i p o f th e am ino g r o u p and th e s u lf o n a m id e
-5 -
g r o u p m ust be m a i n t a i n e d i n s u b s t i t u t e d s u l f a n i l a m i d e s
as w e ll.
b)
A d d i t i o n o f a T h ir d S u b s t i t u e n t i n t h e B en ze n e
n u c le u s.
The i n t r o d u c t i o n o f a t h i r d g r o u p i n t o t h e b e n z e n e
n u c le u s c a u se s a la r g e d ecrea se in a c t i v i t y .
c)
A l t e r a t i o n o f th e S u lf o n a m id e Group
R e p la c e m e n t o f t h e s u lf o n a m id e g r o u p b y NH2 , CN,A3C>3H2
a n d C0NH2 p r o d u c e s i n a c t i v e com p ou n d s.
A l k y l a t i o n o f th e
s u lf o n a m id e g r o u p in g e n e r a l c a u s e s
a d i m i n u t i o n in a c t i v i t y .
N ^ -M eth y l s u l f a n i l a m i d e i s
q u i t e a c t i v e b u t N-^-Butyl s u l f a n i l a m i d e i s o f q u e s t i o n ­
a b le a c t i v i t y .
The l a r g e r t h e a l k y l g r o u p th e g r e a t e r
th e lo s s in a c t i v i t y .
S u b s t i t u t i o n o f one o f t h e
h y d r o g e n ato m s o f t h e s u l f o n a m i d e gro u p by an a r y l o r
s u b s t i t u t e d a r y l group h a s a v a r i a b l e e f f e c t .
The
r e s u l t i n g compounds p o s s e s s th e t y p e s t r u c t u r e
When X i s
S 0 2N(CH3 ) , S 02NHCH3 , SOgKHg, NOg, o r NHg
t h e r e s u l t i n g compounds a r e a r e a s a c t i v e as
s u lfa n ila m id e in
strep to co cca l in f e c tio n s .
When X i s
-6 -
COOE, t h e a c t i v i t y
is
g r o u p X to a p o s i t i o n
sm a ll.
D isp la cem en t of th e
o r t h o t o t h e a m id ic n i t r o g e n
i n r i n g I I c a u s e s an en h a n ce m e n t i n a c t i v i t y .
d)
A l t e r a t i o n o f Amino Group
S u b stitu tio n
o f t h e amino g r o u p i n th e p a r e n t s t r u c t u r e ,
s u l f a n i l a m i d e , by a l k y l , a r y l ,
a r a l k y l , a c y l and
a l k y l i d e n e groups c a u s e s a n o t i c e a b l e d e c r e a s e i n
b a c te r ic id a l e ffe c tiv e n e s s .
C o n v e r s io n o f th e
amino group t o an a z o g ro u p i s
of l i t t l e
e f f e c t sin c e
th e b od y r e d u c e s t h e a zo group t o an am ino g ro u p
th ereb y g e n e r a tin g s u lfa n ila m id e .
The ab o ve summary i n d i c a t e s
c o r r e l a t i o n b e tw e e n
t o what e x t e n t a
s t r u c t u r e and t h e r a p e u t i c e f f e c t
o f t h e s u l f a n i l a m i d e s had b e e n r e a c h e d a t th e tim e
th is
r e s e a r c h was b e g u n .
S in c e
t h o s e compounds form ed
by s u b s t i t u t i n g o n e o f th e h y d r o g e n atom s o f t h e
s u lf o n a m id e g ro u p by a s u b s t i t u t e d b e n z e n e n u c l e u s
w ere th e o n ly g r o u p w h ich p o s s e s s e d an a c t i v i t y
g r e a t e r th an s u l f a n i l a m i d e ,
th e
d e sir a b ility
of
p r e p a r i n g more compounds o f a s i m i l i a r s t r u c t u r e was
fo r c e fu lly e v id e n t.
I t was f e l t
th a t th e
r e p la c e m e n t
of t h e b en zen e r i n g by a p y r i d i n e o r q u i n o l i n e n u c l e u s
m ig h t l e a d t o compounds o f an a c t i v e n a t u r e .
Compounds
o f t h i s ty p e w o u ld be s u l f a n i l y l d e r i v a t i v e s o f th e
-7
am ino p y r i d i n e s and q u i n o l i n e s .
The b a c t e r i o s t a t i c n a t u r e o f a l i m i t e d number o f
d e r i v a t i v e s o f d iam in o p y r i d i n e s i s w e l l known.
The
t r e a t m e n t o f g e n i t o u r i n a r y i n f e c t i o n s by means o f
2 , 6 - d i a m i n o - 3 - p h e n y l a z o p y r i d i n e was d e v e l o p e d by
O s tr o m isle n sk y T h is
drug i s commonly c a l l e d "P yrid ium 4 .
In 1 9 2 8 Dorn and D ie d r ic h " ^ p r e p a r e d an a c t i v e com­
pound h a v i n g th e s t r u c t u r e 2 * - b u t o x y p y r i d y l - 5 , 5 ' - a z o - 2 ,
6 - d ia m in o p y r i d i n e .
More r e c e n t l y B i n z and S c h ic k h, U
p repared a s e r i e s o f c o u p lin g p r o d u cts o f 3 ,5 -d ia m in o
p y r i d i n e w h ic h a r e c l a i m e d t o be a c t i v e b a c t e r i c i d e s .
In th e t r e a t m e n t o f p r o to z o a n I n f e c t i o n s o f t h e
b l o o d s tr e a m d e r i v a t i v e s o f a m i n o q u i n o l i n e s h a v e proven
very e f f e c t i v e .
The s p e c i f i c a n t i m a l a r i a l a c t i o n o f
6 - m e t h o x y - 8 - ( a - m e t h y l - d - d i e t h y l a m i n o b u t y l ) a m in o q u in o lin e ,
commonly known a s
" P la sm o q u in e " h a s b e e n r e c o g 12
n iz e d fo r se v e r a l y e a r s .
I t i s u s e d e x t e n s i v e l y in
c o n j u n c t i o n w i t h q u i n i n e in t h e t r e a t m e n t o f m a l a r i a .
C l o s e l y r e l a t e d c h e m i c a l l y t o t h e a m in o q u i n o l i n e s
are th e a m in o a c r id in e s .
S e v e r a l o f t h e s e and t h e i r
d e r i v a t i v e s su c h a s ' • P r o f l a v i n e " a n d " A e r i f l a v i n e "
a r e known t o p o s s e s s s t r o n g a n t i s c e p t i c a c t i o n
a g a i n s t v a r io u s s t r a i n s o f s t r e p t o c o c c i in v iv o a s
w e ll a s in v i t r o .
8-
The o b j e c t o f t h e f i r s t p a r t o f t h i s r e s e a r c h was
t h e p r e p a r a t i o n o f s u l f a n i l y l d e r i v a t i v e s o f t h e amino
q u i n o l i n e s and p y r i d i n e s .
The e f f e c t o f t h e s u b s t i t u t i o n
o f th e p y r i d i n e o r q u i n o l i n e n u c l e u s f o r one o f th e
a m id ic h y d r o g e n s o f s u l f a n i l a m i d e c o u l d i n t h i s way
be d e t e m i n e d .
PART I - CHAPTER I I
DISCUSSION OP EXPERIMENTAL
-9 CHAPTER I I - PART I
D isc u ssio n
o f E x p erim en tal
The P r e p a r a t i o n o f Amino P y r i d i n e s
2 -A m ln o p y r ld in e
2 -A m in o p y r id in e
i s m ost r a p i d l y p r e p a r e d by th e
a m in a t io n o f p y r i d i n e w i t h sodam ide a c c o r d i n g t o t h e
d i r e c t i o n s o f C h i c h i b a b i n , 13
y ie ld
U s i n g t h i s method a
o f 40% was o b t a i n e d .
3 - A m ln o p y r id ln e
Two p r i n c i p a l m e th o d s a r e a v a i l a b l e f o r th e
p r e p a r a t i o n o f t h i s com pound.
N ic o tin ic
a c id
14
may r e a d i l y be c o n v e r t e d by means o f t h e a c i d c h l o r i d e
to i t s e t h y l e s t e r . T h e
a m id e , o b t a i n e d from t h e
e s t e r by th e a c t i o n o f am m o n ia ca l m e th y l a l c o h o l ,
when s u b j e c t e d t o t h e Hofmann r e a c t i o n r e a d i l y g i v e s
3 -a m in o p y r id in e .^ 6
A much l e s s
t e d i o u s m eth od,
a sou rce o f 2 - c h l o r - 5 - n i t r o p y r id in e i s
if
a v a ila b le ,
is
t h e r e d u c t i o n o f t h i s compound by means o f z i n c d u s t
and s u l f u r i c d i r e c t l y
to 3 -a m in o p y r id in e .
17
The t e m p e r a t u r e , 1 9 0 ° , u s e d by P o l l a c k in c o n ­
v e r tin g e th y l n ic o tin a te
n e c e s s a r ily h ig h .
to n ic o tin a m id e
seemed u n ­
S in c e th e p r e p a r a tio n of c in c h o n in a -
mide and th e d ia m id e o f q u i n o l i n e 2 , 4 - d i c a r b o x y l i c acid ^ ®
fr o m t h e c o r r e s p o n d i n g e t h y l e s t e r s
is
effected
in
-1 0 -
q u a n tita tiv e y ie ld
by t h e a c t i o n o f am m on iacal m e th y l
a l c o h o l a t 6 0 ° i t was b e l i e v e d t h a t t h e same m ild c o n d i t i o n s
w o u ld c o n v e r t e t h y l n i c o t i n a t e t o n i c o t i n a m i d e .
U n d er
t h e s e c o n d i t i o n s , h o w e v e r , e t h y l n i c o t i n a t e gav e a w h i t e
s o l i d i n q u a n t i t a t i v e y i e l d , w h ich was n o t th e e x p e c t e d
n ic o tin a m id e.
it
When r e c r y s t a l l i z e d f o u r t im e s from b e n z e n e
gave & m e l t i n g p o i n t o f 1 2 8 - 1 3 0 ° .
The m e l t i n g p o i n t
rep o rted fo r n ic o tin a m id e i s 1 2 1 -1 2 2 °.
1 9-20
A n a ly sis f o r
p e r c e n t n i t r o g e n by Dumas gave a v a l u e one p e r c e n t l o w e r
th a n t h a t r e q u i r e d by n i c o t i n a m i d e .
F u r th e r m o r e t h e
Hofmann d e g r a d a t i o n u s i n g an e x c e s s o f sodium h y p o b r o m ite
gave no 5 -a m in o p y r id in e .
P o lla ck
f o u n d t h a t an e x c e s s
o f so d iu m h y p o b r o m ite w as n e c e s s a r y i n c o n v e r t i n g n i c o t i n ­
amide t o
the a m in e .
I t w as d e c id e d t o abandon t h i s m ethod
o f p r e p a r in g 3 - a m i n o p y r i d i n e and t o u s e
p y r id in e
in ste a d .
2 -c h lo r -5 -n itr o -
N i t r a t i o n o f 2 -a m in o p y r id in e a c c o r d in g
t o C h i c h i b a b i n * s d i r e c t i o n s 21 r e s u l t s
i n a m ix t u r e o f
5 - n i t r o - 2 - a m i n o p y r i d i n e and 5 - n i t r o - 2 - a m i n o p y r i d i n e w h ic h
is
r e a d i l y s e p a r a te d i n t o i t s com p on en ts.
D ia z o tiz a tio n
o f 5 - n i t r o - 2 - a m i n o p y r i d i n e in fu m ing h y d r o c h l o r i c a c i d
y ie ld s
5 - n i t r o - 2 - c h l o r p y r i d i n e , 21
pound w i t h z i n c d u s t and d i l u t e
R e d u c t io n o f t h i s com-
s u lf u r ic a c id x
produces
a 40% y i e l d o f 3 - a m i n o p y r i d i n e .
4 -Amino p y r i d i n e
T h i s compound may r e a d i l y be s y n t h e s i z e d by t h e a c t i o n
-1 1 -
o f a q u eo u s ammonia on p y r i d y l - p y r i d i n i u m d i c h l o r i d e .
The l a t t e r compound i s
22
r e a d i l y p r e p a r e d by a l l o w i n g d r y
p y r id in e and t h io n y l c h l o r i d e t o s ta n d f o r a p e r io d o f
one week a t room t e m p e r a t u r e .
t o K o e n ig s and G r e i n e r ‘S
a r e supp osed t o f o llo w
fo llo w in g c o u r se :
H
The r e a c t i o n s a c c o r d i n g
th e
H
N C1
By a l t e r i n g th e method o f i s o l a t i o n o f t h e 4 - a m l n o p y r i d i n e
a b e t t e r y i e l d th an t h a t r e p o r t e d by t h e o r i g i n a l w o r k e r s
was o b t a i n e d .
2 -A c ety la m in o -5 a m ln o p y r ld in e
A c e t y l a t i o n o f 2 - a m i n o - 5 - n i t r o p y r i d i n e f o l l o w e d by
r e d u c tio n o f th e n i t r o grou p y i e l d s 2 -a c e ty la m in o -5 -a m in o
-1 2 -
p y r id in e .
F o r t u n a t e l y a s u p p ly o f t h i s compound w as
a v a i l a b l e and i t was n o t s y n t h e s i z e d i n th e c o u r s e o f
th is
in v e stig a tio n .
B efo re use i t
was r e c r y s t a l l i z e d
fro m t o l u e n e .
The P r e p a r a t i o n o f A m i n o q u i n o l i n e s .
5 -A m ln o q u ln o lln e
3 - A m i n o q u in o lin e i s
p e r h a p s th e m o st d i f f i c u l t o f
t h e p y r -a m in o q u i n o l i n e s t o p r e p a r e .
I t may be fo rm ed
b y r e d u c t i o n o f th e c o r r e s p o n d i n g n i t r o compound w h ic h
is
fo iroed i n p o or y i e l d b y th e c o n d e n s a t i o n o f o r t h o
a m in o b e n z a ld e h y d e w i t h m e t a z o n ic a c i d .
m eth od e m p lo y e d by Renshaw and F ried m an
93
18
The r e c e n t
f o r the
s y n t h e s i s o f 3 - a m i n o - q u i n o l i n e I s much b e t t e r .
sists
I t co n ­
o f t h e c o n v e r s i o n o f 3 - b r o m q u in o lin e t o 5 - a m in o -
q u i n o l i n e by means o f a q u eo u s ammonia a t 2 0 0 ° .
i n v e s t i g a t i o n t h e l a t t e r method w as u s e d .
In t h i s
A c c o r d in g t o
t h e l i t e r a t u r e , 3 - a m i n o q u i n o l i n e h a s two m e l t i n g p o i n t s
8 3 ° and 9 4 ° .
Friedm an o b s e r v e d t h e l o w e r m e l t i n g p o i n t
b u t n e v e r th e h ig h e r .
The m a t e r i a l o b t a i n e d by t h e a u t h o r
m e l t e d a t 9 3 - 9 4 ° when r e c r y s t a l l i z e d from l i g r o i n b u t
upon s o l i d i f i c a t i o n
r e m elted a t 8 2 - 8 3 ° .
B z . A m in o q u in o lin e s
The a m i n o q u i n o l i n e s c o n t a i n i n g t h e amino g ro u p
-1 3 -
in t h e b e n z e n o i d p o r t i o n o f t h e q u i n o l i n e r i n g a r e p r e ­
p a r e d by r e d u c t i o n o f t h e c o r r e s p o n d i n g n i t r o q u i n o l i n e s .
In 1 9 2 9 , D ik s c h o o r n
04
made a d e t a i l e d s t u d y o f t h e r e d u c t i o n
o f 5 and 8 - n i t r o q u i n o l i n e .
He f o u n d t h a t when s t a n n o u s
c h l o r i d e and h y d r o c h l o r i c a c i d w ere u s e d t h e r e s u l t i n g
amino compounds were c o n t a m in a t e d w i t h l a r g e amounts o f
c h lo r o -a m in o q u in o lin e s,
r i n g s u b s t i t u t i o n h a v in g o c c u r r e d
d u r in g th e c o u r s e o f t h e r e d u c t i o n .
w orker to o b t a in th e y i e l d s
A t t e m p t s by t h i s
o f 5 and 8 - a m i n o q u i n o l i n e
r e p o r t e d b y C la u s and S c h n e l l
95
u s i n g i r o n and d i l u t e
a c e t ic a c id f o r r e d u c tio n , f a i l e d .
M ost o f t h e n i t r o -
q u i n o l i n e was r e c o v e r e d u n c h a n g e d .
The u s e o f a l c o h o l i c
so d iu m p o l y s u l f i d e
r e d u c t i o n w ere a l s o
in e ffe c tiv e .
and e l e c t r o l y t i c
D ik s c h o o r n f i n a l l y
i r o n and 50% a c e t i c
T h is m ethod i s
te d io u s.
r e s o r t e d t o th e u s e o f
a c id , o b ta in in g y i e l d s o f about 7 5 $ .
l o n g and i s o l a t i o n o f th e amine i s r a t h e r
In t h i s
in v e stig a tio n ,
5 , 7 , and 8 - n i t r o q u i n o l i n e
w ere r e d u c e d c a t a l y t i c a l l y In a s u i t a b l e menstruum by
means o f Raney n i c k e l .
The y l e l d 3
f o r 5 and 8 -a m in o ­
q u i n o l i n e w ere o n l y 75 and 69?b r e s p e c t i v e l y b u t th e r a p i d i t y
o f th e p r o c e d u r e a n d t h e e a s e o f i s o l a t i o n
make t h i s m eth od s u i t a b l e .
o f th e p r o d u c t s
7 -a m in o q u i n o l i n e was o b t a i n e d
i n a 95% y i e l d by th e ab o v e m e th o d .
I t m e lte d a t 7 4 - 7 5 .5 °
i n a c c o r d w i t h t h e m e l t i n g p o i n t g i v e n by Harrier^6 and
n
25
n o t a t 1 8 9 ° a s d e s c r i b e d by e a r l i e r w o r k e r s .
-1 4 -
The 6 -a m ln o q u i n o l i n e u s e d In t h i s work was p r e p a r e d
fro m c r u d e 6 - n i t r o q u i n o l i n e
Skraup r e a c t i o n . 2*^
o b t a i n e d by means o f th e
The l i m i t e d c a p a c i t y o f t h e l o w -
p r e s s u r e h y d r o g e n a t o r and t h e n e c e s s i t y o f u s i n g a b s o l u t e l y
pure s t a r t i n g m a t e r i a l s r e s t r i c t s
th e u s e o f c a t a l y t i c
r e d u c tio n to r e l a t i v e l y sm a ll q u a n t i t i e s o f m a t e r i a l .
A m ethod was d e v i s e d w hereby th e c r u d e 6 - n i t r o q u i n o l i n e
fro m th e Skraup r e a c t i o n c o u l d be r e d u c e d by means o f i r o n
and h y d r o c h l o r i c a c i d t o 6 - a m i n o q u i n o l i n e .
The o v e r a l l
y i e l d , b a s e d on p a r a - n i t r a n l l i n e , was 4 5 $ .
The P r e p a r a t i o n o f S u l f a n l l y l D e r i v a t i v e s
o f A m in o p y r id in e s and A m i n o q u i n o l i n e s
The s u l f a n i l a m i d e s were p r e p a r e d by c o n d e n s i n g r e ­
c r y s t a l l i z e d a c e t y l s u l f a n i l y l c h l o r i d e 28 w i t h th e
a p p r o p r i a t e amine i n p y r i d i n e s o l u t i o n .
5-N 4 - A c e t y l -
s u l f a n i l a m i d e - 2 - a c e t y l a m i n o p y r i d i n e was p r e p a r e d from
5 - a m i n o - 2 - a c e t y l a m i n o p y r i d i n e by B a u e r ’ s 22 m ethod em­
p lo y in g a c e to n e .
The crude a c e t y l d e r i v a t i v e s w e re r e ­
c r y s t a l l i z e d from e t h a n o l o r p r o p a n o l .
In c a s e s where
no s u i t a b l e s o l v e n t c o u ld b e f o u n d , t h e p r o d u c t s were
w ash ed and d r i e d b e f o r e a n a l y s i s ,
t i o n o f th e f r e e a m in e .
o r p r e p a r e d by a c e t y l a -
In a l l c a s e s , e x c e p t t h a t o f
2 - U ^ - a c e t y l s u l f a n i l a m i n o p y r i d i n e , rem o v a l o f th e a c e t y l
-1 5
g ro u p was e f f e c t e d by b o i l i n g f o r a h a l f h o u r w i t h 12$
h y d ro c h lo r ic a c i d .
T h is t r e a t m e n t c a u s e s r u p t u r e o f
t h e s u lf o n a m id e l i n k a g e when a p p l i e d t o 2-N4 - a c e t y l s u l fa n ila m id o p y r id in e.
When t h e h y d r o l y s i s was c a r r i e d o u t
in a l c o h o l i c h y d r o c h lo r id e a c i d s o l u t i o n , th e
s u lf o n a m id e
l i n k r em a in e d i n t a c t .
S e v e r a l a t t e m p t s were made t o p r e p a r e 4 - s u l f a n i l a m i d o p y r i d i n e , by v a r i o u s m eth ods o f h y d r o l y s i s o f 4 -N 4 - a c e t y l su lfa n ia m id o p y r id in e .
A lc o h o lic h y d r o c h lo r ic a c id
h y d r o l y s i s c a u s e d r u p tu r e o f th e s u lf o n a m id e l i n k a g e I n
th is c a se .
A queous a c i d h y d r o l y s i s h a d a s i m i l i a r e f f e c t .
PART I
•EXPERIMENTAL
-1 6 -
4 - A m l n o p y r ld ln e
P y r i d y l - p y r i d i n i u m - d i c h l o r i d e ( 8 6 g . ) was s u s p e n d e d
in 500 c c .
o f c o n c e n t r a t e d ammonium h y d r o x i d e s o l u t i o n
and h e a t e d in a s t e e l a u t o c l a v e a t 1 5 0 ° f o r e i g h t h o u r s .
The r e a c t i o n m i x t u r e was t h e n e v a p o r a t e d t o a volum e o f
100 c c .
A f t e r th e a d d itio n
h y d ro x id e,
th e r e a c t i o n m i x t u r e was steam d i s t i l l e d w i t h
s u p e r h e a te d steam a t 2 0 0 ° .
when th e d i s t i l l a t e
d is tilla te
o f 20 g . o f s o l i d p o t a s s i u m
The d i s t i l l a t i o n
was no l o n g e r b a s i c .
was h a l t e d
The a c i d i f i e d
was e v a p o r a t e d t o d r y n e s s , d i s s o l v e d i n a s m a l l
amount o f w a t e r , made a l k a l i n e w i t h c o n c e n t r a t e d p o t a s s i u m
h y d ro x id e s o l u t i o n ,
and c o n t i n u o u s l y e t h e r e x t r a c t e d .
The
4 - a m i n o p y r i d i n e , 2 5 g . ( 7 3 ^ ) , c r y s t a l l i z e d from t h e e t h e r
i n a p u re fo r m , m . p . 1 5 6 - 1 5 8 ° .
report a y ie ld
o f prod u ct.
K o e n ig 3 a n d G r e i n e r ^
o f 61% u s i n g a d i f f e r e n t m ethod o f i s o l a t i o n
-1 7 -
5 - . 7 - . and 8 -A m ln o q u ln o lln e
7 -N itro q u in o lin e
(1 0 g . ,
0 . 0 5 8 m o le ) d i s s o l v e d in
100 c c . o f a c e t o n e , was r e d u c e d i n a lo w p r e s s u r e P a r r
hyd rogen ator in
Raney n i c k e l .
th e p r e se n c e of 0 .6 g .
( 0 . 0 0 1 m o le ) o f
R e d u c t io n was com ple i n one h o u r .
The
a c e t o n e w as t h e n a l l o w e d t o e v a p o r a t e a f t e r f i l t r a t i o n
of th e c a t a l y s t .
The am ine s e p a r a t e d a s an o i l w h ich
soon s o l i d i f i e d .
Upon r e c r y s t a l l i z a t i o n
from w a t e r ,
l i g h t y e l l o w n e e d l e s w ere o b t a i n e d ; y i e l d : 8 g . ( 9 5 $ ) ,
m .p . 7 4 - 7 5 . 5 ° .
The same p r o c e d u r e was u s e d f o r 5 - and 8 - a m in o q u i n o l i n e , u s i n g 95$ e t h y l a l c o h o l as th e s o l v e n t .
A
c o n s i d e r a b l e am ount o f b l a c k t a r r y b y - p r o d u c t was fo rm ed
i n t h e l a t t e r tw o c a s e s .
R e c r y s t a l l i z a t i o n from l i g r o i n
and p e t r o le u m e t h e r gav e y i e l d s o f 7 5 and 69$ r e s p e c t i v e l y .
-1 8 -
6 - A m l n o q u in o lln e
In a 3 l i t e r round b o t to m e q u ip p e d w i t h a r e f l u x
c o n d e n s e r , th e f o l l o w i n g r e a g e n t s were a dd ed i n t h e i n ­
d ic a te d order:
220
11 6
240
112
g.
g.
g.
g.
co n cen tra ted s u lfu r ic a c id
a r s e n ic o x id e
o f g ly c e r in e
p a r a n itr a n ilin e
A f t e r t h o r o u g h l y m ix i n g ,
t h e r e a c t i o n f l a s k was h e a t e d
i n an o i l b a t h k e p t a t 1 5 5 - 1 6 0 ° f o r a p e r i o d o f t h r e e h o u r s .
The r e a c t i o n m ix t u r e was th e n p o u r e d i n t o 3 l i t e r s
of c o ld
w a t e r and a s m a l l amount o f dark t a r r y m a t e r i a l rem oved
by f i l t r a t i o n .
The f i l t r a t e was t r e a t e d w i t h 4 0 $ sodium
h y d r o x i d e s o l u t i o n u n t i l I t was j u s t s l i g h t l y a c i d i c t o
Congo r e d .
The cru d e 6 - n i t r o q u i n o l i n e w h ic h s e p a r a t e d
from t h e h o t s o l u t i o n was f i l t e r e d o f f and w ashed w i t h
th re e p o r tio n s o f hot w a te r .
Upon m aking th e f i l t r a t e
b a s i c , a l a r g e lump o f b l a c k t a r wa3 fo r m e d .
p r o d u c t was d r i e d i n th e oven a t 7 0 ° .
The cru d e
I t w e ig h e d 1 4 0 g .
The cru d e 6 - n i t r o q u i n o l i n e was p l a c e d in a 5 0 0 c c
E r l e n m e y e r f l a s k e q u ip p e d w i t h an e f f i c i e n t s t i r r e r and
m ix e d w i t h 20 0 c c o f w a t e r c o n t a i n i n g 14 c c . o f c o n ­
c e n tr a te d h y d ro c h lo r ic a c i d .
The r e a c t i o n m ix t u r e was
h e a t e d t o 9 0 ° and in th e c o u r s e o f one h o u r 1 70 g . o f
i r o n powder was a d d ed in a p o r t i o n w i s e m an ner.
The
t e m p e r a t u r e was t h e n m a i n t a i n e d a t 9 5 ° f o r an a d d i t i o n a l
-1 9 -
two h o u r s .
A t th e e n d o f t h i s tim e t h e m ix t u r e was made
b a s i c w it h so d iu m c a r b o n a t e and upon c o o l i n g , f i l t e r e d .
A f t e r d r y i n g in t h e o v e n , t h e c r u d e am ine w as e x t r a c t e d
from th e i n o r g a n i c m a t e r i a l w i t h e t h e r i n a S o x h l e t
ap p aratu s.
The e t h e r was t h e n a l l o w e d t o e v a p o r a t e and
th e r e s i d u e vacuum d i s t i l l e d .
was 53 g . ( 4 5 $ ,
147 -1 5 0 °.
The y i e l d o f pure p r o d u c t
b a s e d on p a r a n i t r a n i l i n e ) ; b . p . / 2 mm.
-2 0 -
2 -S u lfa n lla m ld o p y r id in e
A c e t y l s u l f a n i l y l c h lo r id e
(4 g . ) w ere d i s s o l v e d in 34 c c .
5 c c . o f dry p y r i d i n e .
(1 0 g . )
and 2 - a m i n o p y r i d i n e
o f aceton e c o n ta in in g
Upon s t a n d i n g o v e r n i g h t 5 g . o f
a l m o s t pure p r o d u c t s e p a r a t e d a s a w h i t e d e p o s i t .
The
f i l t r a t e upon d i l u t i o n w i t h w a t e r gave an a d d i t i o n a l 4 g .
F o r a n a l y s i s i t was r e c r y s t a l l i z e d fr o m a c e t o n e a s s m a l l
w h it e n e e d l e s ; m .p . 2 2 6 - 2 2 7 ° .
Removal o f th e a c e t y l g ro u p was e f f e c t e d by t r e a t i n g
1 . 0 g . o f the c r u d e a c e t y l compound w i t h 1 0 c c . o f e t h a n o l
and 2 c c • o f 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 .
A fter
r e f l u x i n g f o r tw e n ty m in u t e s , th e r e a c t i o n m ix t u r e was
d i l u t e d w i t h w a t e r and made b a s i c w i t h ammonium h y d r o x i d e .
I t was r e c r y s t a l l i z e d from e t h y l a l c o h o l ; y i e l d , 0 . 6 7 g .
(75?0,* m .p . 1 9 0 - 1 9 1 ° .
21-
5 -S u lfa n lla m ld '0 -2 -a m ln o p y r ld ip e
To 3 . 0 g . o f 2 - a c e t y l a m i n o - 5 - a m l n o p y r i d i n e s u s ­
p en d ed In 20 c c . o f a c e t o n e and 3 . 5 c c . o f d ry p y r i d i n e ,
a c e t y ls u lf a n i ly l c h lo r id e
( 4 . 0 g . ) was a d d e d .
a d d itio n o f th e a c id c h lo r id e ,
Upon t h e
th e amine d i s s o l v e d com­
p l e t e l y and th e s o l u t i o n t u r n e d o r a n g e .
A f t e r sta n d in 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 p r o d u c t p r e c i p i t a t e d
a s a w h i t e amorphous p o w d er.
w a t e r added t o th e f i l t r a t e
o f th e p r o d u c t .
w e ig h e d 6 . 0 g .
T h is was f i l t e r e d o f f and
t o p r e c i p i t a t e th e r e m a in d e r
The c r u d e p r o d u c t was f a i r l y pure and
( 9 4 %) .
S i n c e 5 -N 4 - a c e t y l s u l f a n i l a m i d o -
2 - a c e t y l a m i n o p y r i d i n e c o u l d n o t be s a t i s f a c t o r i l y p u r ­
i f i e d by c r y s t a l l i z a t i o n ,
a n a l y s i s by a c e t y l a t i o n
a sam ple was o b t a i n e d f o r
of 5 -S u lfa n ila r a id o -2 -a m in o -
p y r id in e w ith a c e t i c a n h y d r id e .
I t s e p a r a t e d from th e
a c e t i c a n h y d r id e in t h e form o f -s m a ll, w h i t e n e e d l e s j
m .p . 2 8 8 - 2 9 1 ° w i t h d e c ' n .
The a c e t y l g r o u p was rem oved from 5-N 4 - a c e t y l s u l f a n l l a m i d o - 2 - a c e t y l a m i n o p y r i d i n e by r e f l u x i n g 1 . 0 g . o f th e
c r u d e p r o d u c t w i t h 2 0 c c . o f 12% h y d r o c h l o r i c a c i d f o r
-2 2 -
one h a l f - h o u r .
Upon n e u t r a l i z i n g th e r e a c t i o n m ix tu r e
w i t h d i l u t e ammonium h y d r o x i d e ,
th e f r e e amine s e p a r a t e d
in th e form o f w h i t e n e e d l e s fr o m th e h o t s o l u t i o n .
may be r e c r y s t a l l i z e d from w a t e r o r e t h y l a l c o h o l ;
y d . 0 . 6 5 g . ( 8 7 % ) ; m .p . 2 1 0 - 2 1 1 ° .
It
-2 3 -
3 -S u lfa n ila m id o p y r id in e
3 - A m in o p y r id in e ( 3 . 3 g . ) was d i s s o l v e d
d ry p y r i d i n e .
To t h i s
in 3 0 c c . o f
s o lu tio n , a c e t y ls u lf a n i ly l c h lo r id e
( 8 . 0 g . ) was added p o r t i o n w i s e .
A f t e r h e a t i n g f o r two
h o u r s on th e ste a m b a t h , th e r e a c t i o n m ix t u r e was c o o l e d
and p ou red i n t o S50 c c . o f c o l d w a t e r .
s e p a r a t e d a s a w h i t e , am orph ous,
so lid .
The p r o d u c t
I t was w ash ed
t h o r o u g h l y w i t h w a t e r and a c e t o n e t o remove any a d h e r in g
p y r id in e .
in so lu b le
The y i e l d o f cru d e was 7 . 5 g ( 7 5 $ ) .
in a l l th e common s o l v e n t s .
It is
For a n a ly s is a
s m a ll amount o f th e cru d e was w a sh ed w i t h h o t a l c o h o l
and d r i e d a t 9 0 ° ; m e l t i n g p o i n t 2 7 2 - 2 7 5 ° w i t h d e c ’ n .
The rem o v a l o f th e a c e t y l g r o u p was a c c o m p l i s h e d
by r e f l u x i n g 3 . 0 g . o f cru d e 3 - N ^ - a c e t y l s u l f a n i l a m i d o p y r id in e w ith 30 c c .
o f 12$ h y d r o c h lo r ic a c id f o r a
p e r i o d o f one h a l f - h o u r .
The r e a c t i o n m ix t u r e was th e n
n e u t r a l i z e d w i t h d i l u t e ammonium h y d r o x i d e .
The p r o d u c t
p r e c ip it a t e d a s a w h ite c r y s t a l l i n e
The y i e l d
was p r a c t i c a l l y q u a n t i t a t i v e .
p ow d er.
The cru d e p r o d u c t i s
i n s o l u b l e i n w a t e r and a l l t h e l o w e r a l c o h o l s .
I t may
be r e c r y s t a l l i z e d fr o m amyl a l c o h o l b u t t h i s i s a c co m p a n ie d
by p a r t i a l d e c o m p o s i t i o n .
For a n a l y t i c a l p u rp oses,
it
was p u r i f i e d by w a s h in g w i t h h o t a l c o h o l and th e n d r y i n g
a t 9 0 ° , m .p . 2 4 8 - 2 5 1 ° w i t h d e c * n .
-2 4 -
S u lfa n ila m ld o q u ln o lln e s
The f o l l o w i n g m ethod was u s e d in p r e p a r i n g t h e s u l f a n ily l d e r iv a tiv e s of 3 -,
5 -,
6 - , and 8 - a m i n o q u i n o l i n e :
F i v e grams o f a m i n o q u i n o l i n e was d i s s o l v e d i n 25
c c . o f dry p y r i d i n e .
c h lo r id e
To t h i s s o l u t i o n a c e t y l s u l f a n i l y l
(8 g . ) was added and th e m ix t u r e h e a t e d on th e
ste a m b a t h f o r two h o u r 3 .
A fte r c o o lin g th e s o l u t i o n ,
i t was p ou red i n t o 3 0 0 c c . o f w a t e r .
The p r e c i p i t a t e d
p r o d u c t was f i l t e r e d and th e n w a sh ed w i t h a c e t o n e t o
remove any r e m a in in g p y r i d i n e .
used f o r r e c r y s t a l liz a t io n
The y i e l d and s o l v e n t
a r e shown i n th e f o l l o w i n g
ta b le :
Compound
$ Y ie ld
3-]\l4 - a c e t y l s u l f a n i l a m i d o q u i n o l i n e
S o lv e n t
— 91
E th y l A lc o h o l
5 -N ^ -a c e ty ls u lfa n ila m id o q u in o lin e — 72
E th y l A lco h o l
6 - K ^ - a c e t y l s u l f a n i l a m i d o q u i n o l i n e - - 69
n -P ro p y l A lc o h o l
8-K 4 - a c e t y l s u l f a n i l a m i d o q u i n o l i n e
E th y l A lc o h o l
— 60
Removal o f th e a c e t y l gro u p t o fo r m th e c o r r e s p o n d i n g
s u l f a n i l a m i d o q u i n o l i n e s was c a r r i e d o u t i n a q u e o u s
h y d r o c h lo r ic a c id in a l l fo u r c a s e s .
The p r o c e d u r e u s e d
was t h e same a s d e s c r i b e d i n th e p r e p a r a t i o n o f 3 - s u l f a n i l a m id o p y r id in e .
The y i e l d s
o f t h e f r e e a m in e s and th e
s o l v e n t u s e d f o r t h e i r r e c r y s t a l l i z a t i o n a r e shown i n t h e
fo llo w in g ta b le :
-2 5 -
Compound
$ Y ie ld
S o lv e n t
3 -S u lfa n ila m id o q u in o lin e
91
E th y l A lc o h o l
5 -S u lfa n ila m id o q u in o lin e
76
E th y l A lc o h o l
6 -S u lfa n ila m id o q u in o lin e
81
E th y l A lco h o l-W a ter
8 -S u lfa n ila m id o q u in o lin e
87
E th y l A lc o h o l
The m e l t i n g p o i n t s and a n a l y t i c a l d a ta o f a l l t h e
compounds l i s t e d
Page 2 6 .
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Part I
BIBLIOGRAPHY
-2 7 -
PART I
BIBLIOGRAPHY
1.
Domagk:
2.
T re fo u el, N i t t l ,
3.
T r e f o u e l , N i t t i , and B o v e t :
4.
B u t t l e , G ray, and S t e p h e n s o n :
5.
M ietzsc h :
6.
D e u ts c h e med. W o h n s c h r ., 6 1 , 25 0 ( 1 9 3 5 )
and B o v e t : Compt. r e n d . S o c . B i o l . ,
1 2 0 , 756 (1 9 3 5 )
A nn. I n s t . P a s t e u r , 5 8 ,
30 (1 9 3 7 )
L ancet I ,
1286 (1 9 3 6 )
B e r . 7 1 , 15 ( 1 9 5 8 )
B auer and R o s e n t h a l :
U . S . T r e a s u r y D ep artm en t
P u b l i c H e a l t h R ep’ t s
53, 40 (1938)
7.
I.G .F .
: G er. 8 1 7 , 0 3 4 j C .A . 3 2 , 17 14 ( 1 9 3 8 )
8.
C r o s s l e y , N o r t h e y , and H u l t q u i s t :
J .A .C .S .,
2222 ( 1 9 3 8 )
9.
P y r id iu m C o rp ’ n : B r i t . 3 1 1 , 3 4 9
10.
G er. 5 4 3 , 2 8 8
11.
B in z and S c h i c k h :
12.
O e ttin g e n :
13.
C h ic h ib a b in and S e i d e : J . R u s s . p h y s . c h e m .,
4 6 , 1216 (1 9 1 4 )
14.
"Organic S y n t h e s i s " C o l l e c t e d V o l . , 378
15.
S p a th and S p i t z e : B e r . , 5 9 , 1 4 7 7 ,
16.
P o l l a c k : M o n a t s c h . , 1 6 , 54 ( 1 8 9 5 )
17.
B in z and S c h i c k h : B e r . , 6 8 , 3 1 5 ( 1 9 3 5 )
60,
U . S . 2 , 1 4 5 , 5 7 9 ; C . A . , 2 6 ,4 1 3 3 ( 1 9 3 2 )
" T h e r a p e u tic A g e n t s o f Q u i n o l i n e Group"
18.
Renshaw and F r ie d m a n : J . A . C . S . ,
19.
Meyer:
(1 9 2 6 )
61 , 3320 (1 9 3 9 )
M o n a t s c h ., 2 3 , 9 0 0 ( 1 9 0 2 )
106
-2 8 -
20.
Camps: A r c h . Pharm ., 2 4 0 , 3 5 4 ( 1 9 0 3 )
21.
C h i c h i b a b i n : J . R u s s . p h y s . c h e m ., 4 6 , 1 2 3 4 ( 1 9 1 4 )
22.
K o e n ig s and G r e in e r : B e r . 6 4 , 1049 ( 1 9 3 1 )
23.
B a r g e l l i n i and S e t t i n i :
24.
D ik s c h o o r n : R ec. T r a v . C h im ., 4 8 , 153 ( 1 9 2 9 )
25.
C la u s and S c h n e l l : J . P r a k t . Chem., 5 3 , 1 1 3 ( 1 8 9 6 )
26.
Hamer: J . Chem. S o c . , 1 1 9 , 1434 ( 1 9 2 1 )
27.
K n e u p p e l: B e r . 29 , 7 0 4 ( 1 8 9 6 )
28.
"O rganic S y n t h e s e s " C o l l e c t e d V o l . , 8 .
29.
B auer: J .A .C .S ., 6 1 ,
O az. Ch. I t . ,
613 ( 1 9 3 9 )
601,
(19 23 )
PART I I - CHAPTER I
INTRODUCTION
-29-
CHAPTER I - PART I I
INTRODUCTION
The p u r p o se o f the s e c o n d p a r t o f t h i s
research
was th e p r e p a r a t i o n pf p y r i d i n e and q u i n o l i n e a n a l o g u e s
of is a tin .
I t was f e l t t h a t compounds o f t h i s t y p e
c o n ta in in g a d ik e t o p y r r o lid in e n u cle u s fu se d to a
n i t r o g e n h e t e r o c y c l e w ou ld be o f v a l u e
in th e s y n t h e s i s
o f n a p h t h y r i d i n e s and p h e n a n t h r o l i n e s by means o f t h e
P fitz in g e r r e a c tio n .
COOH
RCOCE
HOOC
R
CO— CO
a
A .
(in
RCOCH-z
A r e v i e w o f th e l i t e r a t u r e
p y r id in e s
( I ) a r e known.
shows t h a t no d i k e t o - p y r r o l o
U n t i l 1 9 3 8 , compounds o f ty p e I I
-3 0 -
h ad n o t b e e n r e p o r t e d b u t i n t h a t y e a r W ielan d ^ s y n t h e s i z e d
3 -p y r r o lo
[3 ,2 - fj
q u in o lin e .
2
s u g g e s t e d by P a t t e r s o n .
T h is n o m e n c la t u r e i s
CH —CH
X
"The f o l l o w i n g p l a n s i s s u g g e s t e d : f o r th e nu m bering
o f t h e s u b s t i t u t e n t s r e t a i n t h e i r A r a b ic n u m e r a ls ; f o r
th e nu m b erin g o f th e p a r e n t c o m p ln e n t s t a r t w i t h th e s i d e
1 , 2 and l e t t e r t h e s i d e s o f th e c o m p le x w i t h s m a l l i t a l i c
or Roman l e t t e r s .
L e t t e r e v e r y s i d e , e v e n w here t h e r e
a r e no numbered p o s i t i o n s , a s f u s i o n may o c c u r on any
sid e .
Then u s e o n l y su ch o f t h e s e s y m b o ls a s a r e r e ­
q u i r e d t o i n d i c a t e where th e f u s i o n h a s o c c u r r e d .
P lace
them in t h e h e a r t o f th e nam e. A fe w e x a m p le s w i l l make
th e p la n c l e a r :
g
\
XV
f
/ V
NV " \
Benzojjb] quinoline
Benzojjf} quinoline
NAphtho [2,1-gQquinoline
In th e l a s t ex am p le t h e o r d e r o f t h e numbers 1 , 2 o r 2 , 1
i n d i c a t e s w h e t h e r th e nu m b erin g o f t h e s u b s t i t u t e n t
( n a p h t h a l e n e ) t r a v e l s w i t h o r a g a i n s t t h a t o f th e p a r e n t
on th e s i d e where f u s i o n o c c u r s . "
-3 1 -
The im p o r ta n c e o f i s a t i n
in th e p r e p a r a t i o n o f a
l a r g e number o f dye i n t e r e d i a t e s prom pted much r e s e a r c h
c o n c e r n i n g i t s m eth ods o f p r e p a r a t i o n .
The t h r e e m ost
3 4 5
im p o r t a n t m ethods a r e due t o San dm eyer. * *
The f i r s t
c o n s is t s of fo u r s t a g e s .
D i p h e n y l t h i o u r e a , form ed from
a n i l i n e and ca rb on d i s u l f i d e , when t r e a t e d w i t h l e a d
c a r b o n a t e and h y d rog en c y a n i d e g i v e s N , N ' - d i p h e n y l c y a n o -fo rm a m id in e.
ammonium s u l f i d e
T h is i s
c o n v e r t e d by means o f y e l l o w
i n t o a t h i o - a m i d e , w h ic h on h e a t i n g w i t h
c o n c e n t r a t e d s u l f u r i c a c i d fo rm s i s a t i n - a l p h a - a n i l i d e .
T h is compound can be h y d r o l y s e d t o i s a t i n .
S
CN
II
/
NH
I
C-NH
/
NH
!=N -(^
-3 2 -
The s e c o n d method c o n s i s t s o f th e f o r m a t i o n i f
is o n itr o s o -
d i p h e n y l a c e t& m id in e by t h e c o n d e n s a t i o n o f a n i l i n e ,
c h l o r a l h y d r a t e and h y d r o x y la m in e h y d r o c h l o r i d e in
n e u t r a l a q u eo u s s o l u t i o n .
CO
%so4
--------
Neutral
S o l’n v
C = N - C 6 Hg
NH
CCl-CH NOH
Acid
S o l'n
NHC0CH=N0H
■co
I
CO
%so4
NH
The a m id in e s t r u c t u r e i s
cen tra ted su lfu r ic
c o n v e r t e d by h e a t i n g i n c o n ­
a c i d t o i s a t i n a lp h a a n i l i d e .
t h i r d method i s a m o d i f i c a t i o n o f th e s e c o n d .
a q u e o u s medium, th e
a c e ta n ilid e ,
The
In a c i d i c
same r e a c t a n t s form i s o n i t r o s o -
i n s t e a d o f th e a m i d i n e .
in c o n c e n t r a t e d s u l f u r i c
T h i s , on h e a t i n g
a c i d form s i s a t i n - b e t a - i m i n e
-3 3 -
w h ic h i s
r e a d i l y h y d r o l y s e d to i s t a i n
in a q u e o u s s o l u t i o n ,
The m o st r e c e n t m ethod u s e d in t h e f o r m a t i o n o f i s a t i n s
c o n sists
in th e r i n g c l o s u r e o f c y a n o f o r m a n i l i d e s in th e
p r e s e n c e o f alum inum c h l o r i d e .
C.
CO
I
CO
A l C lr
/
NH
‘ NHDOCN
Of th e f o u r m eth o d s m e n t io n e d a b o v e , method t h r e e
was s e l e c t e d f o r th e a t t e m p t e d s y n t h e s i s o f i s a t i n s
d e r i v e d from th e a m i n o p y r i d i n e s and a m i n o q u i n o l i n e s f o r
th e f o l l o w i n g r e a s o n s .
The f i r s t method i s
t o o l o n g and
i n a d d i t i o n o n ly h a l f th e o r i g i n a l amine i s
con verted to
th e c o rr e sp o n d in g i s a t i n .
The s e c o n d m ethod was a l s o
n e g l e c t e d f o r th e same r e a s o n .
The l a s t method i n v o l v e s
a r i n g c l o s u r e u s i n g aluminum c h l o r i d e a s a c a t a l y s t .
The P r i e d e l s - C r a f t s r e a c t i o n
i s n o t a p p lic a b le to q u in 7
o lin e or p y r id in e d e r i v a t i v e s ,
c o m p le x f o r m a t i o n
rem ov in g the aluminum c h l o r i d e and t h u s i n h i b i t i n g
r e a c tio n .
The Sandm eyer i s a t i n
s y n t h e s is in v o lv in g th e
i n t e r m e d i a t e f o r m a t i o n o f an i s o n i t r o s o a c e t y l d e r i v a t i v e
i s a p p l i c a b l e w i t h few e x c e p t i o n s t o a l l
su b stitu te d
-3 4 -
a n i l i n e s c o n t a i n i n g a t l e a s e one f r e e
t o t h e amino g r o u p .
p o s it io n orth o
A t te m p ts by Sandmeyer^ t o p r e p a r e
the i s o n i t r o s o a c e t y l d e r i v a t i v e s o f a lp h a and b e t a - n a p h t h y l a m in e , and m eta p h e n y le n e d ia m in e l e d t o d a r k , brown s u b ­
s t a n c e s w h ic h w ere n o t f u r t h e r i n v e s t i g a t e d .
The i s o ­
n i t r o s o a c e t y l d e r i v a t i v e s o f th e n i t r a n i l i n e s , ®
or 2 , 4 , - d i c h l o r a n i l i n e , orth o a n i s i d i n e ,
2 ,4 ,-d ib r o m o
and para p h e n e t -
i d i n e 5 do n o t u n d e rg o r i n g c l o s u r e by t h i s m e th o d .
The r e m a in d e r o f t h i s t h e s i s
is
d e v o t e d t o th e
p r e p a r a t i o n o f th e i s o n i t r o s o a c e t y l d e r i v a t i v e s o f th e amino
p y r i d i n e s and a m i n o q u i n o l i n e s , and t h e i r r i n g c l o s u r e .
r e a s o n s f o r o n ly p a r t i a l s u c c e s s i n t h i s
d isc u sse d .
The
d ir e c tio n i s a lso
PART I I - CHAPTER I I
DISCUSSION OF EXPERIMENTAL
-35-
CHAPTER I I - PART I I
DISCUSSION OF EXPERIMENTAL
(A)
P r e p a r a tio n o f I s o n i t r o s o a c e t y l D e r iv a t iv e s
The r e a c t i o n b e tw e e n a n i l i n e ,
c h lo r a l hyd rate,
and h y d r o x y la m in e t o form i s o n i t r o s o a c e t a n i l i d e
s u p p o s e d t o t a k e p l a c e in th e f o l l o w i n g w ay:
Is
C h lo r a lo x im e,
fo r m e d by o x im a t io n o f c h l o r a l , u n i t e s w i t h a n i l i n e by
th e e l i m i n a t i o n
o f one m o l e c u l e o f h y d r o c h l o r i c a c i d ,
fo r m in g , su p p o se d ly ,
T h is i s
I f th e
d ic h lo r o -iso n itr o so a c e ta n ilid e •
r a p id ly h y d ro ly se d to i s o n i t r o s o a c e t a n i l i d e .
o r ig in a l so lu tio n
is not s u ffic ie n t ly a c id ic ,
th r e e m o le c u le s o f h y d r o c h lo r ic a c id are e lim in a t e d
b e tw e e n a n i l i n e and c h l o r a l o x i m e t o form i s o n i t r o s o d ip h e n y l-a c e ta m id in e .
NHg
NHCC12 CH=N0H
cci 3 ch= koh
►-
1THCOCH=NOH
h2o
---- >•
The h i g h p r i c e o f h y d r o x y la m in e h y d r o c h l o r i d e l e d
-36-
Sandm eyer
5
t o t r y h y d r o x y la m in e s u l f a t e , a s o l u t i o n o f
w h ic h can be o b t a i n e d by t r e a t i n g sod iu m n i t r i t e
w i t h so d iu m b i s u l f i t e .
d isu lfo n ic
The r e s u l t a n t so d iu m s a l t o f th e
a c i d o f h y d r o x y la m in e can be c o n v e r t e d t o
h y d r o x y la m in e s u l f a t e by b o i l i n g i t w i t h d i l u t e
a c id .
so lu tio n
su lfu r ic
The s o l u t i o n c o n t a i n s much so d iu m s u l f a t e .
The
a d d itio n
o f c h l o r a l h y d r a t e and a n i l i n e t o th e b o i l i n g
s o lu tio n
r e su lts
in th e p r e c i p i t a t i o n
of iso n itr o so ­
a c e ta n ilid e .
The tim e - c o n s u m in g p r e p a r a t i o n o f th e h y d r o x y la m in e
s u lfa te
s o l u t i o n prom pted M arvel and H iers® t o i n v e s t i g a t e
t h e r e a c t i o n u s i n g h y d r o x y la m in e h y d r o c h l o r i d e .
T hese
w o r k e r s fo u n d t h a t th e a d d i t i o n o f s o d iu m s u l f a t e
necessary.
I t h a s more th a n a s a l t i n g - o u t e f f e c t .
sa tu ra ted so lu tio n
is
o b ta in e d .
is
o f so d iu m c h l o r i d e
If a
i s u s e d , no p r o d u c t
In th e p r e p a r a t i o n o f th e i s o n i t r o s o a c e t y l
d e r i v a t i v e o f 5 - a m i n o q u i n o l i n e by t h e a u t h o r ,
s u l f a t e was a l s o fo u n d n e c e s s a r y .
sodium
The d e s i r e d p r o d u c t
was o b t a i n e d when t h e r e a c t i o n was run in t h e p r e s e n c e
o f th e in o r g a n ic s a l t .
H ow ever, when t h e r e a c t i o n was
c o n d u c t e d in i t s a b s e n c e no p r o d u c t was o b t a i n e d .
In th e a t t e m p t e d p r e p a r a t i o n o f th e i s o n i t r o s o a c e t y l
d e r i v a t i v e s o f the a m i n o p y r i d i n e s and q u i n o l i n e s th e m o la r
p r o p o r t i o n s s u g g e s t e d by M a rv e l and H ie r s® in th e
-37-
p r e p a r a t i o n o f i s o n i t r o s o a c e t a n i l i d e w ere u s e d .
Iso n itr o so a o e ty la m in o p y r id in e a
2 - A m in o p y r id in e f a i l e d t o u n d e r g o i s o n i t r o s o a c e t y l a t i o n .
I t was r e c o v e r e d u n ch a n g e d from th e r e a c t i o n m i x t u r e , by
co n tin u o u s e t h e r e x t r a c t i o n .
F a i l u r e t o r e a c t in t h i s
c a s e was n o t u n e x p e c t e d s i n c e 2 - a m in o p y r id i n e
its
in many o f
r e a c t i o n s d o e s n o t e x h i b i t th e u s u a l c h a r a c t e r i s t i c s
o f a t y p i c a l p rim ary a r o m a t ic a m in e .
I t s c h e m ic a l b e h a v io r
may b e s t be e x p l a i n e d on th e b a s i s o f t a u t o m e r i s m , one
o f t h e a m in o id h y d ro g e n atom s m i g r a t i n g t o t h e r i n g
n i t r o g e n , fo r m in g a p y r i d o n e - i m i n e s t r u c t u r e .
Numerous
d e r i v a t i v e s o f b o t h fo rm s h a ve b e e n i s o l a t e d .
E
S i n c e 4 - a r a in o p y r i d in e h a s a s t r o n g e r te n d e n c y than
2 - a m i n o p y r i d i n e t o r e a c t in th e p y r i d o n e - i m i n e fo r m , no
a t t e m p t was made t o form i t s
iso n itr o so a c e ty l d e r iv a tiv e .
S u b s t i t u e n t s in th e 3 - p o 3 i t i o n
in p y r i d i n e b e h a v e
e s s e n t i a l l y a s t h e y w ould i n a b e n z e n e n u c l e u s .
3 - a m in o -
p y r i d i n e , l i k e a n i l i n e , u n d e r g o e s norm al d i a z o t i z a t i o n ,
and shows no t e n d e n c y t o r e a c t i n a t a u t o m e r i c im in e fo r m ,
as i s ,
of c o u r s e , e x p e c t e d .
3 -Iso n itr o so a c e ty la m in o p y r id in e
38-
i3
r e a d i l y fo rm ed by th e a c t i o n o f c h l o r a l and h y d r o x y la m in e
on 3 -a m in o p y r i d i n e .
F o r 2 , 6 - d i a m i n o p y r i d i n e , one may w r i t e t h r e e s t r u c t u r e s :
H
E
I t i s r e a d i l y n o t i c e a b l e t h a t in a l l
th ree
s t r u c t u r e s th e
amino g r o u p , a s d i s t i n c t from t h e im in o g r o u p , i s u n i t e d
t o a c a r b o n atom w h ich i s
i n t u r n u n i t e d t o th e a d j a c e n t
c a rb o n atom by a d o u b le b o n d .
On m ig h t e x p e c t , t h e r e f o r e ,
t h a t one o f th e 3 p o s i t i o n s w ould be r e a c t i v e .
fo u n d t o be s o .
stru ctu re
T h is i s
S e id e and T itov^ ® i n w r i t i n g a b o u t t h e
o f 2 , 6 - d i- s u b s t it u t e d p y r id in e s s t a t e
"Der
E i n t r i t t e i n e s z w e i t e n S u b s t i t u e n t e n in den P y r id in - K e r n
v e r l e i h t ih n e n d i e F a h i g k e i t , r a s c h und q u a n t i t a t i v e A z o K u p p lu n g e n , N i t r o s i e r u n g , H a l o g e n i e r u n g , K o n d e n s a t io n m it
F o r m a ld e h y d e , O x y d a tio n d u rch E i s e n c h l o r i d e i n z u g e h e n ,
e s s t e i g e r t in u n v e r g l e i c h l i c h e m Masse d ie K i t r i e r b a r k e i t
u s w ."
In th e s u b s t i t u t i o n r e a c t i o n s m e n t io n e d , t h e su b ­
s t i t u e n t e n t e r s i n th e 3 p o s i t i o n .
A r e a c t io n o f 2 ,6 -d ia m in o
p y r i d i n e more germane t o t h i s r e s e a r c h i 3 i t s
w ith e t h y l a c e to a c e ta te
r e a c tio n
t o form a n a p h t h y r i d i n e
T h is
-3 9 -
i s fu rth er in d ic a tio n
o f th e l a b i l e n a t u r e o f one o f th e
h y d ro g en atom s in t h e 3 p o s i t i o n .
CSjCOCBgCOOCgHg
V
OH
I t was f e l t t h a t i f
the i s o n i t r o s o a c e t y l d e r i v a t i v e o f
2 , 6 - d i a m i n o p y r i d i n e c o u ld be p r e p a r e d , i t s
w ould be e a s i l y a c c o m p l i s h e d .
r in g c lo su r e
U n fo r tu n a te ly a tte m p ts to
p r e p a r e i t l e d t o a dark b l a c k s o l i d from w h ic h no pure
compound c o u l d be i s o l a t e d .
I so n ltr o so a c e ty la m ln o -^ u ln o lin e s
5 - A m i n o q u in o lin e when t r e a t e d w i t h c h l o r a l and h y d r o x y l amine h y d r o c h l o r i d e
gave a s m a l l y i e l d o f th e e x p e c t e d
iso n itr o so a c e ty la m in o q u in o lin e .
No p r o d u c t r e s u l t e d
when th e r e a c t i o n was run in th e a b s e n c e o f so d iu m s u l f a t e .
6 - A m in o q u in o lin e f o r a s th e I s o n i t r o s o a c e t y l d e r i v a t i v e i n
q u a n tita tiv e y ie ld .
W ith th e i s o m e r i c 8 - a m i n o q u i n o l i n e a
b la c k t a r r e s u l t e d w h ic h was n o t i n v e s t i g a t e d .
(B )
R ing C lo s u r e t o I s a t i n S t r u c t u r e
When 3 - i s o n i t r o s o a c e t y l a m i n o - p y r i d i n e was t r e a t e d
-4 0 -
w it h 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 t 1 0 0 ° , a d i k e t o p y r r o l o p y r i d i n e w as n o t o b t a i n e d .
The 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 upon d i l u t i o n o f t h e a c i d s o l u t i o n and a d j u s t ­
ment o f th e pH t o b e tw e e n 5 and 6 .
I f one c o n s i d e r s
r i n g c l o s u r e a s an i n t r a m o l e c u l a r s u b s t i t u t i o n , f a i l u r e
in t h i s
ca se i s not u n exp ected .
M o n o -su b stitu te d p y r id in e
d e r i v a t i v e s c o n ta in in g th e s u b s t i t u e n t in th e 5 p o s it io n
do n o t u n d e r g o f u r t h e r s u b s t i t u t i o n
fr e e orth o p o s i t i o n s .
c a n n o t be n i t r a t e d .
in e i t h e r o f t h e two
3 - A m i n o p y r i d i n e , f o r e x a m p le ,
3 -C h lo ro -p y r id in e i s n it r a t e d
w i t h d i f f i c u l t y , b u t th e n i t r o g ro u p e n t e r s in th e 5 p o sitio n .
Two a t t e m p t s w ere made t o c o n v e r t 5 - i s o n i t r o s o a c e t y l a m in o q u in o lin e to a d i k e t o - p y r r o l o - q u i n o l i n e .
was c o n d u c t e d a t 8 0 ° f o r a h a l f - h o u r .
so lu tio n
The s u l f u r i c a c i d
t u r n e d r e d , u s u a l l y an i n d i c a t i o n o f r i n g c l o s u r e ,
b u t upon d i l u t i o n and n e u t r a l i z a t i o n
m ix tu r e th e
sta te.
The f i r s t
o f th e r e a c tio n
s t a r t i n g m a t e r i a l was o b t a i n e d i n an impure
A fter p u r ific a tio n
it
p o s s e s s e d th e same d e c o m p o s i­
t i o n p o i n t a s t h e o r i g i n a l w i t h th e same c h a r a c t e r i s t i c
e v o lu tio n
of gas.
I t gav e no c o l o r ch a n g e when d i s s o l v e d
in d i l u t e
sodium h y d r o x id e s o l u t i o n ,
r i n g c l o s u r e had n o t o c c u r r e d .
in d ic a tin g th at
The s e c o n d a t t e m p t t o
c l o s e t h e r i n g c o n d u c t e d a t 1 0 0 ° f o r f i f t e e n m i n u t e s , ga ve
-4 1
r e s u l t s a n a l o g o u s t o th e f i r s t .
The p o o r y i e l d o f th e
i n t e r m e d i a t e i s o n i t r o s o a c e t y l a m i n o - q u i n o l i n e and th e
n e g a t i v e r e s u l t s o b t a i n e d when t h e a b o v e a t t e m p t s were
made t o e f f e c t r i n g c l o s u r e , d i s c o u r a g e d f u r t h e r e f f o r t s
to prepare t h i s d i k e t o - p y r r o l o - q u i n o l i n e .
6 -I s o n itr o s o a c e ty la m in o -q u in o lin e , u n lik e i t s
r e a d ily undergoes r in g c lo s u r e .
iso m e r,
The b e s t c o n d i t i o n s f o r
th e f o r m a t i o n o f 1 , 2 - d i k e t o - 3 - p y r r o l o
[3 ,2 -f]
q u in o lin e
w ere d e t e r m in e d by c o n d u c t i n g t h e r e a c t i o n a t v a r i o u s
tem p era tu res f o r v a r y in g le n g t h s o f tim e .
I t was fo u n d
t h a t h e a t in g in c o n c e n tr a te d s u l f u r i c a c id a t 9 4 ° f o r
fifte e n
m in u t e s ga v e an Q0% y i e l d o f p r o d u c t .
Low er
te m p e r a t u r e s r e s u l t e d in o n l y p a r t i a l r i n g c l o s u r e ,
m ig h t a p p e a r t h a t r i n g c l o s u r e
It
in t h i s c a s e w o u ld h a v e an
e q u a l chance o f o c c u r r in g a t p o s i t i o n
5 o r 7 o f th e
q u i n o l i n e r i n g , r e s u l t i n g i n a m ix t u r e o f two i s o m e r i c
d ik e to -p y r r o lo -q u in o lin e s.
CO — CO
H
NHC0CH=N0H
CO
-4 2 -
A c t u a l l y , a3 w i l l be shown, the r i n g c l o s e s e x c l u s i v e l y
in p o s i t i o n 5 .
when t r i c y c l i c
A r e v i e w o f th e l i t e r a t u r e
compounds a r e p r e p a r e d from a s u b s t i t u t e d
n a p h t h a le n e o r q u i n o l i n e by r i n g c l o s u r e ,
two p o s s i b l e
shows t h a t
iso m ers i s form ed.
o n l y one o f th e
T h is may be i l l u s t r a t e d
by th e Skraup r e a c t i o n a s a p p l i e d t o 2 - a m i n o - n a p h t h a l e n e •
In t h i s c a s e r i n g c l o s u r e o c c u r s a t p o s i t i o n
1.
12
So s t r o n g
i s th e t e n d e n c y f o r r i n g c l o s u r e t o o c c u r a t p o s i t i o n 1 ,
t h a t i f a s u b s t i t u e n t such a s Cl o r NOg i s
p o sitio n ,
it
p r e s e n t in t h i s
13
i s e l i m i n a t e d u r in g t h e r e a c t i o n .
The
Dobner r e a c t i o n w i t h
Cl (NOo)
Skra-qp
2 - a m i n o - n a p h t h a l e n e was shown by B o g e r t and R o b in so n
in v o lv e r in g c lo su r e
in th e 1 p o s i t i o n .
14
6 - A m in o q u in o lin e
when s u b j e c t e d t o t h e S k ra u p r e a c t i o n g i v e s o n ly 4 , 7 p h en a n th ro lin e ,
th e r i n g c l o s i n g a t p o s i t i o n
q u in o lin e n u c l e u s .^
a m e th y l g r o u p ,
th is,
I f th e 5 p o s i t i o n
r in g c lo s u r e f a i l s . ^
5 o f th e
i s b l o c k e d by
In a c c o r d w i t h
5 -8 -d im e th y l-6 -a m in o q u in o lin e f a i l s
in th e Skraup o r Dobner r e a c t i o n .
to
to rea ct
The s i t u a t i o n
is
th e
-4 3 -
same w i t h 7-am ino q u i n o l i n e d e r i v a t i v e s .
Skraup
^
The Skraup
%C
s y n t h e s i s h a s n e v e r been a p p l i e d t o 7 - a m i n o - q u i n o l i n e
b u t h a s been a p p l i e d t o t h e more r e a d i l y p r e p a r e d
2-m ethyl-7-am inoquinoline.
The o n l y p r o d u c t in t h i s c a s e
is 2 -m e th y l-l,7 -p h e n a n th ro lin e , rin g closure occurring
i n t h e 8 p o s i t i o n of th e q u i n o l i n e s t r u c t u r e .
If th is
p o s i t i o n i s b l o c k e d by a m e th y l g r o u p , a s in 7 - a m i n o 8 - m e t h y l - q u i n o l i n e - 5 - s u l f o n i c a c i d , r i n g c lo s u r e fails.-*-6
The l i t e r a t u r e
i s r e p l e t e w i t h many o t h e r examples
o f p r e f e r e n t i a l r i n g c l o s u r e a t one of two p o s s i b l e
p o sitio n s.
Any e x p l a n a t i o n of t h e above phenomenon r e s o l v e s
i t s e l f i n t o a d i s c u s s i o n of o r i e n t a t i o n in n a p h t h a l e n e
and q u i n o l i n e , s i n c e r i n g c l o s u r e i s a form o f s u b s t i t u ­
tio n .
The c o n c e p t o f r e s o n a n c e i s u s e f u l in t h i s
connection.
I have t a k e n t h e l i b e r t y in t h e e n s u i n g
d i s c u s s i o n to apply to q u in o lin e s e v e r a l id ea s developed
by Pauling^*7 t o e x p l a i n t h e c h e m i c a l r e a c t i v i t y o f
-4 4 -
o f n a p h th a len e.
J u stific a tio n
fo r th is
is
i m p l i e d by
P a u l i n g , who in c o m p a r in g q u i n o l i n e and n a p h t h a l e n e ,
says:
"The r e s o n a n c e e n e r g i e s o f p y r i d i n e a n d q u i n o l i n e
a r e a b o u t th e
same a s f o r b e n z e n e and n a p h t h a l e n e ,
r e s p e c t i v e l y , th e same v a l e n c e - b o n d s t r u c t u r e s co n ­
t r ib u t in g fo r th ese m o le c u le s."
A c c o r d in g t o P a u l i n g
th e t h r e e m ost im p o r t a n t v a l e n c e - b o n d s t r u c t u r e s f o r q u i n ­
o lin e are:
He f u r t h e r s t a t e s
th e f o l l o w i n g ,
"A v e r y s i m p l e t r e a t m e n t
o f bond c h a r a c t e r in a r o m a t ic h y d r o c a r b o n s w h ic h l e a d s
t o c o n c l u s i o n s i n g e n e r a l a g r e e m e n t w i t h th e known
c h e m i c a l p r o p e r t i e s o f th e s u b s t a n c e s can b e made on th e
b a s is o f th e u n e x c it e d s t r u c t u r e s o f th e m o le c u le .
may a s s i g n
to e a c h bon d a f r a c t i o n r e p r e s e n t i n g
We
its
do u b le bond c h a r a c t e r , t h i s f r a c t i o n b e i n g t h e r a t i o
o f th e number o f s t r u c t u r e s p l a c i n g a d o u b le bond in t h i s
p o s i t i o n t o th e t o t a l number o f s t r u c t u r e s .
th e f o l l o w i n g r e s u l t s : "
T h is g i v e s
-4 5 -
r 'Y Y *
f
1 2
1 /3
A ^ /3
In be nze ne e ac h bond h a s o n e - h a l f double bond c h a r a c t e r ,
wherea s In q u i n o l i n e the 5 , 6 and 7 , 3 bonds have twot h i r d s and th e 6,7 bond o n e - t h i r d double bond c h a r a c t e r .
"These numbers c a n n o t be g i v e n a q u a n t i t a t i v e i n t e r ­
p r e t a t i o n in term s of c h e m i c a l r e a c t i v i t y ; t h e y do demand,
ho wever, t h a t q u a l i t a t i v e r e l a t i o n s be s a t i s f i e d " .
Re as onin g in t h i s manner, one would e x p e c t t h e bonds
j o i n i n g p o s i t i o n s 5 and 6, and 7 and 8 , t o be more l i k e
double bonds in t h e i r p r o p e r t i e s than the bond j o i n i n g
p o s i t i o n s 6 and 7 .
I f s i m p le r e a c t i o n s a r e chosen
whose mechanisms a r e p r o b a b l y c o n c e r n e d w i t h double
b o n d s , t h e s e may be u s e d t o d e te r m i n e the d e g re e t o
which a g iv en bond a p p r o a c h e s a double bond in c h a r a c t e r .
Such r e a c t i o n s a r e sim p le s u b s t i t u t i o n s , c o u p l i n g
r e a c t i o n s , and t h e Sk raup s y n t h e s i s .
1Q
One would e x p e c t
from the above d i s c u s s i o n the f o l l o w i n g o r i e n t i n g
-46-
effects.
P o s i t i o n o f group
_______ on r i n g
S u b s titu e n t should
enter a t
5
6,8
6
5
7
8
8
5,7
Friedman^-® h a s shown, by t a b u l a t i n g known s u b s t i t u t i o n
r e a c t i o n s o f t h e h y d r o x y - q u i n o l i n e s and a m i n o - q u i n o l i n e s ,
th a t the s u b s t i t u e n t in v a r ia b ly e n t e r s
th e e x p e c t e d
p osition .
In b r i e f ,
lie f
t h e r e i s much j u s t i f i c a t i o n f o r t h e b e ­
t h a t t h e r i n g c l o s u r e o f 6- i s o n i t r o s o a c e t y l a r n i n o -
q n i n o l i n e o c c u r s a t p o s i t i o n 5 , r a t h e r than p o s i t i o n 7
of t h e q u i n o l i n e r i n g .
(G)
R eactions of 1 . 2 -d ik e to -5 -p y r ro lo
[5.2-fl
qu inolin e
The two c a r b o n y l g r o u p s o f i s a t i n a r e q u i t e d i s s im ilia r chem ically.
The one in t h e b e t a p o s i t i o n u n d e r ­
g o e s t h e u s u a l k e t o n i c r e a c t i o n s s u c h a s oxime f o r m a t i o n
and c o n d e n s a t i o n w i t h r e a c t i v e m e t h y l g r o u p s .
The a l p h a
c a r b o n y l gr ou p d o e s n o t e x h i b i t u s u a l k e t o n i c p r o p e r t i e s ,
r e s e m b l i n g s t r o n g l y the c a r b o n y l gr oup i n an a m i d e .
analogy,
By
one would e x p e c t t h a t 1 , 2 - d i k e t o - 3 - p y r r o l o [ 5 , 2 - f j
CHART I
•NH,
NHgOH'HCl
CCI3CHO
r—N H C O C H = N O H
(I)
90
| c o n c . H2 SO4
CO— CO
I
NH
(II)
\
NHgOH
HON=C
(Ill
l / V
'1
B a ( OH) g
CO
COCOOBai
NH
N H,
2
(I V )
-47-
q u ln olin e
keton ic
(II,
C h a r t I ) w o u ld c o n t a i n o n l y one t r u e
grouping.
Oximation o f I I r e s u l t s in the forma­
t i o n o f a monoxime ( I I I )
at p osition 1.
the oximo g r o u p b e i n g i n t r o d u c e d
Because o f th e i n s o l u b i l i t y
of I I ,
the
r e a c t i o n was c o n d u c t e d i n p y r i d i n e and a b s o l u t e a l c o h o l
solu tion .
T h i s oxime i s v e r y s t a b l e
h yd rolytic
reagents.
towa rd a l k a l i n e
I t may be r e c o v e r e d u n c h a n g e d a f t e r
t r e a t m e n t w i t h b o i l i n g 10jo s o d iu m h y d r o x i d e
solution fo r
one h a l f - h o u r .
I s a t i n u n d e r g o e s h y d r o l y s i s when warmed i n a q u e o u s
basic
so lu tio n ,
form ic a c i d .
forms s a l t s
form ing a s a l t o f o r th o -a m in o -b e n z o y l-
Compound I I u n d e r t h e same c o n d i t i o n s
of ( 6 - a m i n o - 5 - q u i n o l y l ) g l y o x y l i c a c i d .
The
p o t a s s i u m s a l t of t h i s a c i d may r e a d i l y be o b t a i n e d by
b o ilin g a solu tion
sev era l m inutes.
in l a r g e ,
of I I in 10% p o t a s s iu m h y d ro x id e f o r
Upon c o o l i n g ,
the s a l t p r e c i p i t a t e s
g l i s t e n i n g p l a t e s , w ith a greenish l u s t r e .
b a r iu m s a l t
(IV , Chart I ) i s
f o r m e d by th e a c t i o n o f
e x c e s s barium hyd ro x id e s o l u t i o n
on I I .
made t o p r e p a r e t h e f r e e a c i d s i n c e
No a t t e m p t was
in aqueous s o l u t i o n
i t r e a d i l y u n d e r g o e s r i n g c l o s u r e and fo rm s I I .
I f an
aqueous s o l u t i o n o f th e p o ta ssiu m s a l t of (6 -a m in o -5 q u in olyl-)
w ith a c e t i c
g l y o x y l i c a c i d i s made o n l y s l i g h t l y a c i d i c
acid,
o f compound I I .
The
t h e r e i s an im m e d ia t e p r e c i p i t a t i o n
-48-
The S y n t h e s i s o f 4 , 7 - P h e n a n t h r o l i n e s by t h e
P f i t z i n g e r R e a c t i o n ______________________________
The P f i t z i n g e r r e a c t i o n i s u s e d i n t h e p r e p a r a t i o n
of s u b s titu te d cin ch on in ic a c id s .
I t in v o l v e s the con­
densation o f ortho-am ino-benzoyl-form ic a cid w ith a
k e t o n e c o n t a i n i n g a r e a c t i v e m e t h y l o r m e t h y l e n e group
a d j a c e n t t o the k e t o n i c c a rb o n y l group.
u s u a l l y condu cted in s t r o n g l y b a s i c
,NH.
The r e a c t i o n i s
solu tion .
■Mg
\ CO
\ R
ftCOCBg,^
-COCOOH
CO
w
COOH
1 , 2-d iketo-3-p yrrolo
[|,2 -f]
q u inolin e
(II)
r e a c t s w ith
a c e t o n e i n t h e p r e s e n c e o f 30%' a q u e o u s s o d iu m h y d r o x i d e
forming 3 - m e t h y l - 4 , 7 - p h e n a n t h r o l i n e - l - c a r b o x y l i c a c id
(V, C h a r t I I ) .
prepare t h i s
W i l l g e r o d t and J a b l o n s k i 2^ a t t e m p t e d t o
compound by a p p l i c a t i o n o f t h e Dbbner r e ­
a c t i o n t o 6- a m i n o - q u i n o l i n e .
These w orkers o b t a in e d a
r e d s o l i d m e l t i n g a t 2 0 5 ° , w h i c h t h e y c l a i m e d was th e
-49-
acid .
In t h e i n v e s t i g a t i o n V was o b t a i n e d a s y e l l o w
n e e d l e s , decomposing a t 3 0 0 ° .
F o l l o w i n g W i l l g e r o d t and
J a b l o n s k i * s d i r e c t i o n s th e a u t h o r o b t a i n e d a r e d d i s h
amorphous s o l i d ,
187-191°.
d e c o m p o s i n g o v e r t h e w id e r a n g e
I t had c e r t a i n p r o p e r t i e s one w ou ld n o t
e x p e c t from th e s t r u c t u r e a s s i g n e d by t h e o r i g i n a l
workers.
It is
insoluble
in d i l u t e
d i s s o l v i n g in b o i l i n g 10$ s u l f u r i c
ar e o b t a i n e d on c o o l i n g .
sen sitiv e,
a c i d s , and upon
a c id , yellow needles
This y e l l o w su b sta n ce i s l i g h t
t u r n i n g brown i n a few d a y s .
only 5 .0 $ n i t r o g e n .
s u l f u r i c a c id the
When warmed s l i g h t l y
I t contains
in c o n c e n tr a te d
o r i g i n a l r ed s u b s t a n c e de c o m p o s e s w i t h
the e v o l u t i o n o f g a s .
S i n c e t h e Dobner r e a c t i o n
t o g i v e in some c a s e s a v a r i e t y o f p r o d u c t s , ^
upon t h e c o n d i t i o n s u n d e r w h i c h t h e
reaction
is
i s n o t s u r p r i s i n g t h a t W i l l g e r o d t and J a b l o n s k i
i s known
depending
run, i t
20
assigned
an i n c o r r e c t s t r u c t u r e t o t h e p r o d u c t t h e y o b t a i n e d i n
th is case.
V
The a u t h o r made s e v e r a l a t t e m p t s t o p r e p a r e
b y the Do bner r e a c t i o n ,
and m o la r q u a n t i t i e s
acid .
a l t e r i n g th e o r d e r o f a d d i t i o n
o f t h e a c e t a l d e h y d e and p y r u v i c
In e v e r y c a s e a r ed s u b s t a n c e was o b t a i n e d
s i m i l i a r t o t h a t d e s c r i b e d by W i l l g e r o d t and J a b l o n s k i .
vVhen 6- a m i n o q u i n o l i n e , a c e t a l d e h y d e , and p y r u v i c a c i d
are a l l o w e d to r e a c t ev en i n c o l d a b s o l u t e a l c o h o l ,
there
CHART I I
CO —r(
^ NH
(II)
\ NA
y
CH3 C0CH3
aq .KaOH
HOOCA
■ch3
V
(V)
\
n
V
-CO
300
1
Unknown
Comp’ d’
(VI)
CH-zCHO
HCl
-NH,
\
CH3 C0C00H
ch3 cho
rKHr
-50-
i s an a l m o s t im m e d i a t e p r e c i p i t a t i o n o f a y e l l o w s o l i d ,
w h i c h on e x p o s u r e t o t h e a i r t u r n s a d e e p r e d .
Compound V, p r e p a r e d by t h e P f i t z i n g e r r e a c t i o n ,
r e a d i l y u n d e r g o e s d e c a r b o x y l a t i o n when h e a t e d above i t s
m eltin g poin t foim ing 3 -m eth y l-4 , 7-phenanthroline
( V I , Cha rt I I ) .
This
compound h a s be e n p r e p a r e d b y
L in d n e r ^ S from 6- a i n i n o q u i n o l i n e , a c e t a l d e h y d e and
pO
h y d r o c h l o r i c a c i d . W i l l g e r o d t and J a b l o n s k i
also
p r e p a r e d t h i s compound by h e a t i n g w i t h s o d a l i m e t h e
r e d s o l i d o b t a i n e d f r o m the Dobner r e a c t i o n .
The a u t h o r
found t h a t h e a t i n g in the a b sen ce o f soda lim e a l s o con­
verted th is
substance
to V I.
I t i s b e lie v e d that W ill­
g e r o d t and J a b l o n s k i 2 *"* d i d n o t o b t a i n V b u t some i n t e r ­
m e d i a t e w h ic h on h e a t t r e a t m e n t r e a r r a n g e s t o form V I .
Mixed m e l t i n g p o i n t d e t e r m i n a t i o n o f s a m p l e s o f VI p r e ­
p a r e d by b o t h me th ods showed no d e p r e s s i o n .
Compound I I c o n d e n s e s w i t h a c e t o p h e n o n e i n t h e
p r e s e n c e o f so diu m h y d r o x i d e s o l u t i o n ,
forming 3 - p h e n y l - 4 ,
7 - p h e n a r i t h r o l i n e - l - c a r b o x y l i c a c i d ( V I I , Chart I I I ) .
T h is compound may a l s o be p r e p a r e d by t h e a c t i o n o f
b e n z a l d e h y d e and p y r u v i c a c i d on 6- a m i n o q u i n o l i n e .
Since th is
20
compound h a s a d e c o m p o s i t i o n p o i n t and n o t
a m elting p o in t,
the
i d e n t i t y o f s a m p l e s o b t a i n e d by b o t h
m et h od s c o u l d n o t be d e t e r m i n e d by a m ix e d m e l t i n g p o i n t .
CHART I I I
CO-CO
RH
(II)
HOOC - r
'C6H5
(VII)
\
fs j^ x x
socig
ch 3 o h
c h 3 o oc
(IX)
(VIII)
\
-CO
2
rCfiH
6n 5
HOOC-
SO C lr
CHgOH*
\
CHgCOCOOH
CgHgCHO
-RH,
\
N '
n
^
-5 1 -
The m e t h y l e s t e r o f b o t h s a m p l e s o f t h e a c i d had t h e
same m e l t i n g p o i n t and mixed m e l t i n g p o i n t d e t e r m i n a t i o n
showed n o d e p r e s s i o n .
the a cid c h lo r id e ,
on th e a c i d .
and V i l a ,
The m e t h y l e s t e r was formed from
o b t a i n e d by t h e a c t i o n o f t h i o n y l c h l o r i d e
As f u r t h e r p r o o f o f t h e i d e n t i t y o f V I I
b o t h ga v e on d e c a r b o x y l a t i o n 3 - p h e n y l - 4 ,
7-p henanthorline
(V III).
B o r s c h e 2^ h a s shown t h a t i s a t i n
condenses w ith
c y c l o h e x a n o n e i n t h e p r e s e n c e o f s o d iu m h y d r o x i d e s o l u ­
tion ,
form ing t e t r a h y d r o s c r i d i n e - 9 - c a r b o x y l i c a c i d .
S e v e r a l a t t e m p t s were made t o c o n d e n s e 1 , 2 - d i k e t o - 3 pyrrolo
(3,2-fl
c a s e the
q u in o lin e w ith cycloh exan one.
In e a c h
s t a r t i n g m a t e r i a l s were r e c o v e r e d u n c h a n g e d .
l\'o a d e q u a t e e x p l a n a t i o n can be g i v e n f o r t h i s ano m al ou s
behavior.
PART I I
EXPERIMENTAL
-52
o
NHCOCH=NOH
Preparation o f 3 -ls o n it r o s o a c e t y la m in o p y r ld ln e
To a s o l u t i o n o f 9* 3 grains o f 3 - a m i n o p y r i d i n e and
18 grams o f c h l o r a l h y d r a t e i n 445 c c .
o f w a t e r , 11 5
grams o f a n h y d r o u s s o di um s u l f a t e w ere a d d e d .
A fte r the
a d d i t i o n o f 22 grams o f h y d r o x y l a m i n e h y d r o c h l o r i d e ,
d i s s o l v e d in 100 c c . o f w a te r ,
the r e s u l t a n t mixture
was r a p i d l y h e a t e d t o b o i l i n g u n d e r a r e f l u x c o n d e n s e r .
The r e a c t i o n m i x t u r e t u r n e d a r e d d i s h - b r o w n .
A fter re-
f l u x i n g f o r f i v e m i n u t e s , t h e s o l u t i o n was a l l o w e d t o
c o o l t o room t e m p e r a t u r e and n e u t r a l i z e d w i t h c o n c e n t r a t e d
ammonium h y d r o x i d e .
da r k- br o wn p l a t e l e t s .
The p r o d u c t s e p a r a t e d i n t h e form o f
The c r u d e p r o d u c t was c r y s t a l l i z e d
fr o m m e t h y l a l c o h o l , H o r i t e b e i n g u s e d t o d e c o l o r i z e
the s o l u t i o n .
It
is
i n s o l u b l e in the u s u a l n o n -p o la r
organic s o lv e n ts but so lu b le
in a l c o h o l .
For a n a l y t i c a l
p u r p o s e s , a s m a l l q u a n t i t y was r e c r y s t a l l i z e d tv ; ic e from
a l a r g e volume o f w a t e r :
le ts;
sm a ll, yellow ish-brow n p la t e ­
m.p. 1 8 4 -1 8 5 ° w it h d e c ’ n .
grams; a f t e r r e c r y s t a l l i z a t i o n
The c r u d e y i e l d was 7 . 5
the y i e l d f e l l
to 4 . 3 grams
or 26$.
A nalysis ;
C alc‘d fo r
!K, 2 5 . 4 4
Found:N, 2 5 .6 9
-5 3 -
NHGOCH=NOH
r^ V S
Preparation of 5 -lso n ltr o s o a c e ty la m ln o q u ln o lln e
To a s o l u t i o n
i n 60 c c .
o f 2 . 0 grams o f 5 - a m i n o q u i n o l i n e d i s s o l v e d
o f w a te r c o n t a i n i n g 0 . 5 cc o f c o n c e n t r a t e d hy­
d r o c h l o r i c a c i d w e re ad d ed 1 6 grams o f a n h y d r o u s s od iu m
s u l f a t e and 2 . 5 grams o f c h l o r a l h y d r a t e .
A f t e r the
a d d i t i o n o f 2 . 9 grams o f h y d r o x y l a m i n e h y d r o c h l o r i d e
d i s s o l v e d i n 1 0 c c . o f w a t e r , t h e m i x t u r e was b o i l e d u n d e r
a r e f l u x c o n d e n s e r f o r one h o u r .
Upon a l l o w i n g 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 , r e d d i s h - b r o w n n e e d l e s
formed.
it
The c r u d e p r o d u c t was p u r i f i e d by d i s s o l v i n g
i n t h e minimum amount o f h o t p y r i d i n e and a d d i n g s i x
volumes of w a t e r .
This
s o l u t i o n was b o n e - b a c k e d , f i l ­
t e r e d and c o o l e d f o r s e v e r a l h o u r s i n t h e i c e - b o x .
L ight
y e l l o w n e e d l e s were o b t a i n e d w h i c h were w ash ed w i t h w a t e r
and a c e t o n e t o remove any a d h e r i n g p y r i d i n e .
acetylarainoquinollne is
solven ts.
in solu b le
5 -Ison itroso-
in the u su a l organ ic
I t d i s s o l v e s i n 1 0 $ s o d iu m h y d r o x i d e s o l u t i o n
from w h i c h i t may be p r e c i p i t a t e d by a c i d i f y i n g
solu tion
t o Congo r e d .
the
The y i e l d was 1 . 2 grams; m . p .
229-231° w ith dec»n.
A n a l y s i s : C a l c ’ d . f o r C^-pgNgOgt K, 1 9 . 5 2
Found: N, 1 9 . 3 4
P r e p a r a t i o n o f 6- i s o n l t r o s o a c e t y l a m l n o g u i n o l l n e
(I)
To a s o l u t i o n o f 3 6 . 5 grams o f 6 - a m i n o q u i n o l i n e i n 1
1 . of w ater c o n ta in in g 2 0 .4 c c . o f con cen trated hydro­
c h l o r i c a c i d , were added 2 9 2 grams o f a n h y d r o u s s odi um
s u l f a t e and 4 5 . 3 grams o f c h l o r a l h y d r a t e .
A f t e r the
a d d i t i o n o f 5 3 . 0 grams o f h y d r o x y l a m i n e h y d r o c h l o r i d e
d i s s o l v e d in 2 4 0 c c . o f w a t e r , t h e m i x t u r e was h e a t e d
to b o i l i n g under a r e f l u x c o n d e n se r.
f o r f i v e m inutes,
A fter reflu xin g
the p r o d u c t s t a r t e d t o p r e c i p i t a t e
and upon r e f l u x i n g f o r an a d d i t i o n a l t e n m i n u t e s ,
the
e n t i r e f l a s k was s o l i d w i t h l i g h t - y e l l o w f l u f f y n e e d l e s .
The r e a c t i o n m i x t u r e was f i l t e r e d h o t and t h e p r o d u c t
w ash ed w i t h t h r e e p o r t i o n s o f b o i l i n g w a t e r t o remove
inorganic s a l t s ,
a f t e r d r y i n g i n t h e oven a t 9 5 ° t h e
p r o d u c t w e i g h e d 5 3 . 0 grams and had a m . p . o f 2 1 0 - 2 1 2 °
w i t h d e c !n .
solven ts.
It is
i n s o l u b l e in a l l the u s u a l organic
For a n a l y t i c a l p u r p o s e s a s m a l l s am pl e was
r e c r y s t a l l i z e d t w i c e fr om a l a r g e volume o f w a t e r .
s e p a r a t e s on c o o l i n g i n t h e fo r m o f l o n g , w h i t e ,
n e e d l e s ; m.p. 2 1 3 -2 1 4 ° w i t h d e c ’n .
It
slen der
The c r u d e y i e l d o f
-5 5 -
5 3 .0 grams ( 9 7 $ ) was q u i t e pu re and was u s e d f o r t h e
next preparation.
A n alysis:
C a l c ' d . f o r C1 1 HgN3 0 g s N, 1 9 . 5 3 ; C,
6 1 . 3 8 ; H, 4 . 2 2
Fou nd: M, 1 9 . 2 4 ; 1 9 . 4 0 ; C, 6 1 . 3 4 ;
H, 3 . 9 2 .
V \/
Preparation of 1 .2 - d lk e t o - 5 - p y r r o lo t 5 . 2 - f l q u in o lin e
(II)
In t h e c o u r s e o f t e n m i n u t e s , 3 7 . 5 grams o f c ru de
6- i s o n i t r o s o a c e t y l a m i n o q u i n o l i n e were added p o r t i o n w i s e
t o 225 grams ( 1 2 2 c c . )
of concentrated s u lfu r ic
acid .
The
r e a c t i o n m i x t u r e t u r n e d a d e e p r e d and t h e t e m p e r a t u r e r o s e
to 6 0 °.
A f t e r p l a c i n g i n a w a t e r b a t h a t 7 0 ° , t h e tem­
p e r a t u r e o f th e b a t h was r a i s e d t o 9 4 ° , o v e r a p e r i o d o f
f i f t e e n m inutes.
th is
The t e m p e r a t u r e was t h e n m a i n t a i n e d a t
t e m p e r a t u r e f o r an a d d i t i o n a l f i f t e e n m i n u t e s .
c o o l i n g t o room t e m p e r a t u r e ,
A fter
t h e r e a c t i o n m i x t u r e was
po u re d w i t h v i g o r o u s s t i r r i n g i n t o 8 0 0 grams o f i c e t o
w h i c h s u f f i c i e n t w a t e r had b e e n ad d ed t o make s t i r r i n g
easy.
S u f f i c i e n t 30/6 s od iu m h y d r o x i d e s o l u t i o n was t h e n
added u n t i l t h e pH o f t h e s o l u t i o n was b e t w e e n 5 and 6
( a c id to b lu e litm u s but b a s ic
t o Congo r e d .
The p r o d u c t
p r e c i p i t a t e d and a f t e r s t a n d i n g o v e m i g h t w a s f i l t e r e d by
su ction .
I t was w ash ed t h o r o u g h l y w i t h h o t w a t e r t o r e ­
move so diu m s u l f a t e .
A f t e r d r y i n g a t 1 0 0 ° , 2 1 . 5 grams
o f a r e d d i s h - o r a n g e powder were o b t a i n e d , c o r r e s p o n d i n g
t o a y i e l d o f 79>o.
It is
i n s o l u b l e in a l l the u s u a l
-5 7 -
organic s o l v e n t s ,
b u t may be r e c r y s t a l l i z e d fr om a 50 $
s o l u t i o n o f p y r i d i n e and w a t e r
in
from w h i c h i t s e p a r a t e s
d a r k - r e d , f e a t h e r y n e e d l e s ; m.p. 3 4 5 -3 4 8 ° w ith d e c ’ n .
A n alysis:
C a l c ’ d . f o r C-j^HgHgOg:
N,
14.14;
C, 6 6 . 6 5 ; H,
3.05
F ou nd:
K,
14.01;.
C, 6 6 . 5 1 ; H,
2.70
O xl m a ti o n of I I
Hydroxylamine h y d r o c h l o r i d e
( 0 . 7 6 grams) was added
t o 1 . 9 8 grams of I I s u s p e n d e d i n 50 c c . o f a 50$ s o l u ­
t i o n o f p y r i d i n e and a b s o l u t e e t h y l a l c o h o l .
t u r e was th e n r e f l u x e d on t h e s t e a m b a t h .
The m i x ­
In a s h o r t
time I I d i s s o l v e d and a f t e r f i f t e e n m i n u t e s th e oxime
(III)
sta r te d to p r e c i p it a t e .
f o r an a d d i t i o n a l two h o u r s .
R e f l u x i n g was c o n t i n u e d
A f t e r c o o l i n g t o room te m­
p e r a t u r e the c r u d e oxim e ( 1 . 5 grams) was f i l t e r e d o f f ,
washed w i t h w a t e r and t h e n a l c o h o l .
The m o t h e r l i q u o r
on s t a n d i n g o v e r n i g h t i n t h e i c e - b o x y i e l d e d an a d d i t i o n a l
0 . 3 grams of o x i m e .
This
oxime i s
i n s o l u b l e in a l l
o r d i n a r y p o l a r and n o n - p o l a r o r g a n i c s o l v e n t s .
be r e c r y s t a l l i z e d fr o m w a t e r .
the
I t cannot
I t may be r e c r y s t a l l i z e d
by d i s s o l v i n g i n v e r y d i l u t e b o i l i n g s o d iu m h y d r o x i d e ,
b o n e - b l a c k i n g , and a c i d i f y i n g t h e b a s i c
acetic
a cid .
It separates
s o lu tio n w ith
i m m e d i a t e l y fro m th e h o t
s o l u t i o n as a y e l l o w amorphous p o w d e r , w h i c h when v i e w e d
unde r t h e m i c r o s c o p e
is
seen to c o n s i s t o f sm all n e e d l e s .
The t o t a l y i e l d was 1 . 7 grams ( 8 0 $ ) ; m . p . 2 3 2 - 2 3 5 ° w i t h dec»
A n alysis:
C a l c ' d f o r C1 1 H7 N3 O2 :
14.14
F ou nd:
N, 1 4 . 0 1
-
59-
COCOOBa^
-NHg
\
P r e p a r a t i o n o f t h e Barium s a l t o f
( 6 -a m in o -5 -q u in o ly l- ) g ly o x y l i c Acid
One gram of I I was d i s s o l v e d i n 3 0 c c .
o f .4 N
b a r i u m h y d r o x id e s o l u t i o n by h e a t i n g f o r s e v e r a l m i n u t e s .
The s o l u t i o n t u r n e d a g r e e n i s h b l a c k b u t upon c o n t i n u e d
b o i l i n g became a l i g h t y e l l o w .
On c o o l i n g ,
the barium
s a l t was o b t a i n e d In t h e fo r m o f y e l l o w n e e d l e s .
It
a p p e a r e d t o be h y g r o s c o p i c s i n c e a sam ple d r i e d o v e r
p o t a s s i u m h y d r o x i d e in a vacuum d e s i c c a t o r r a p i d l y
g a i n e d in w e i g h t when w e i g h e d on a m i c r o - b a l a n c e .
a n a l y s i s , a sample was d r i e d t o c o n s t a n t w e i g h t .
A n alysis:
C a l c ' d f o r (C n H g N g O g J g B a :
Found:
Ba, 2 4 .2 0
Ba,
24.36
Before
-6 0 -
H00C-
/" v A
\
J n
n
V
Preparation o f 3 -m eth y l-4 .7 -p h e n a n th r o lin e 1 - c a r b o x y l l c a c i d (V)
Compound I I ( 4 * 0 grama) was d i s s o l v e d i n 2 1 . 0 c c .
o f 3 0 $ s odi um h y d r o x i d e s o l u t i o n and b o i l e d f o r a s h o r t
tim e.
A f t e r c o o l i n g , 9 c c . o f a c e t o n e and 45 c c . o f
w a t e r w e re ad d ed and the m i x t u r e was h e a t e d f o r ten h o u r s
on t h e
s team b a t h u n d e r r e f l u x .
was t h e n a c i d i f i e d w i t h a c e t i c
The r e a c t i o n m i x t u r e
acid .
brown p r e c i p i t a t e was o b t a i n e d .
To p u r i f y the crude
p r o d u c t i t was d i s s o l v e d i n h o t d i l u t e
bone-blacked, f i l t e r e d ,
of a cetic acid .
procedure fo u r tim e s ,
yellow n e e d le s,
s odi um h y d r o x i d e ,
and p r e c i p i t a t e d from the h o t
s o l u t i o n by t h e a d d i t i o n
th is
Upon c o o l i n g a dark
in solu b le
A fte r rep eating
i t was o b t a i n e d i n th e f o r m o f
in the u s u a l o r g a n ic s o l v e n t s .
The y i e l d o f pure p r o d u c t was 1 . 4 grams ( 3 0 $ ) ; m. p .
2 9 8 - 3 0 0 ° w i t h e v o l u t i o n o f C0 2 »
A n alysis:
C a l c 1d . f o r C1 4 H10N20 2 : N, 1 1 . 7 6 ; C, 7 0 . 5 7 ; H, 4 . 2 3
Found; N, 1 1 . 6 9 ; 1 1 . 6 4 ; C, 7 0 . 3 7 ; H; 3 . 9 3
-6 1 -
-CHg
\
N
Preparation o f 5 -m e th y l-4 .7 -p h e n a n th r o lin e
(V I )
A s m a l l t e s t t u b e c o n t a i n i n g 0 . 4 5 grams o f compound
V was h e a t e d i n a Wood’ s m e t a l b a t h t o 3 0 5 ° .
Carbon
d i o x i d e was e v o l v e d an d a b r o w n i s h v i s c o u s l i q u i d was
formed.
A f t e r t h e f o r m a t i o n o f g a s had s t o p p e d ,
the
tu b e was c o o l e d and t h e c o n t e n t s e x t r a c t e d w i t h t h r e e
5 c c . portion s of e t h e r .
The e t h e r s o l u t i o n was f i l t e r e d
t o remove s m a l l amounts o f i n s o l u b l e m a t e r i a l and e v a p o r a t e d
to d r y n e s s, l e a v i n g a y e llo w c r y s t a l l i n e
resid u e.
This
was d i s s o l v e d i n t h e minimum amount o f b o i l i n g w a t e r ,
bone-blacked,
several hours.
filtered ,
and c o o l e d i n t h e i c e - b o x f o r
The p r o d u c t p r e c i p i t a t e d i n the for m o f
w h i t e n e e d l e s , w h ic h a f t e r a i r - d r y i n g f o r one h o u r had a
m .p . o f 7 4 - 7 6 ° , c o r r e s p o n d i n g t o t h e t e t r a h y d r a t e ^ .
A i r - d r i e d o v e r n ig h t the m e ltin g p o i n t r o s e t o 112-113°
P3
and a g r e e d w i t h t h e m e l t i n g p o i n t f o u n d b y L i n d n e r 15 .
The y i e l d was 0 . 2 1 grams ( 5 6 $ ) .
A n alysis;
C a l c 1d . f o r C1 3 H10N2 : N, 1 4 . 4 3 ; C, 8 0 . 3 8 ; H, 5 . 2 8
Found; N, 1 4 . 2 2 ; C, 8 0 . 4 0 ; H, 4 . 8 5
-62-
HOOC
P r e p a r a tio n of 5 - p h e n y l - 4 . 7 - p h e n a n t h r o l i n e 1 - c a r b o x y l l c a c i d (VII)
Compound
33$ potassium
tim e.
I I ( 4 . 0 gr am s) was d i s s o l v e d i n 12 c c .
hydroxide
To t h i s
s o l u t i o n and b o i l e d f o r a s h o r t
s o l u t i o n w e r e added 24 c c . o f a b s o l u t e
a l c o h o l and 4 . 5 grams o f a c e t o p h e n o n e .
f o r s i x hours
of
on th e s t e a m b a t h t h e
was d i l u t e d w i t h 3 0 c c .
A fter refluxin g
r e a c t io n m ixture
o f w a t e r and s te am d i s t i l l e d
remove th e a l c o h o l and e x c e s s a c e t o p h e n o n e .
to
Upon making
t h e s o l u t i o n s l i g h t l y a c i d t o Congo r e d w i t h 1 0 $ s u l f u r i c
acid,
th e c r u d e p r o d u c t was o b t a i n e d a s a brown powder
w e i g h i n g 4 . 3 grams ( 7 1 $ y d . )
The c r u d e p r e p a r a t i o n was
used f o r f u r t h e r s y n t h e t i c work.
For a n a l y t i c a l pur­
p o s e s a s m a l l s a m p le was p u r i f i e d b y th e method d e s c r i b e d
f o r compound V.
A fter p u r ific a tio n
i t was o b t a i n e d in
t h e form o f s m a l l , b r o w n i s h - y e l l o w n e e d l e s ; m . p . 2 9 5 - 2 9 8 °
w ith d e c 'n .
A n alysis:
C a lc *d . f o r c l g H1 2 K2 0 2 ! N» 9 , 3 3
F ou nd : N, 9 . 5 6
-63-
>
P reparation o f l-C arbom eth oxy-3-p henyl-4.
7 - P h e n a n t h r o l l n e ( IX)
Compound V II ( 0 . 7 8 grams) was r e f l u x e d f o r one h a l f h o u r with 10 c c . o f t h i o n y l c h l o r i d e .
A f t e r r e m o v i n g th e
e x c e s s t h i o n y l c h l o r i d e by d i s t i l l a t i o n u n d e r r e d u c e d
pressure,
20 c c . o f m e t h y l a l c o h o l was added and t h e mix­
ture reflu x ed fo r f iv e m inutes.
A s m a l l amount o f
m a t e r i a l r e m a i n e d u n d i s s o l v e d and was removed by f i l t e r i n g
the b o i l i n g s o l u t i o n .
yellow n e e d le s
Upon c o o l i n g th e f i l t r a t e ,
lig h t
s e p a r a t e d , w h i c h were p r o b a b l y t h e h y d r o ­
c h l o r i d e of' t h e e s t e r .
The a i r d r i e d h y d r o c h l o r i d e o f
t h e e s t e r was s u s p e n d e d in 5 c c . o f c h l o r o f o r m t o which
3 c c . of 10% s o d iu m h y d r o x i d e were a d d e d .
t h o r o u g h l y in a s e p a r a t o r y f u n n e l ,
A f t e r shaking
the c h loroform la y e r
was removed and e v a p o r a t e d t o d r y n e s s , l e a v i n g a l i g h t
y e l l o w r e s i d u e w eig h in g 0 . 4 0 grams.
c r u d e p r o d u c t was 1 4 7 - 1 5 0 ° .
t i o n s f r o m m e th y l a l c o h o l ,
The m . p . o f t h e
A f t e r two r e c r y s t a l l i z a ­
t h e e s t e r was o b t a i n e d a s
s le n d e r w h it e n e e d l e s ; m.p. 1 5 1 - 1 5 2 ° .
A nalysis:
Calc * d . f o r OgQii-^^NgOg.
» 8 .92
Pou nd: N, 8 . 7 6
-64-
Preparation of 5 -p h e n y l-4 .7 -p h e n a n th r o lin e
(V III)
A v e r y s m a l l q u a n t i t y o f compound V was d e c a r b o x l a t e d
by h e a t i n g i n a Wood’ s m e t a l b a t h t o 3 0 5 ° f o r s e v e r a l
m inutes.
The brown s o l i d r e s i d u e was d i s s o l v e d i n 15
c c . o f b o i l i n g 1 0 % s u l f u r i c a c i d , b o n e - b l a c k e d and
filtered .
The c o o l f i l t r a t e was made b a s i c w i t h 1 0 $
so diu m h y d r o x i d e .
A w h ite f l o c c u l e n t p r e c i p i t a t e formed,
w h i c h was r e c r y s t a l l i s e d t w i c e fr om e t h y l a l c o h o l .
Since
the product s t i l l
it
p o ssessed a l i g h t greenish tin g e ,
was r e c r y s t a l l i z e d t w i c e from l i g r o i n ; w h i t e p l a t e s w i t h
a y e llo w t i n g e ; m .p. 1 8 7 - 1 8 8 ° .
A nalysis t
C alc ’ d f o r
10.93
Found :N, 1 0 . 6 7
Part
II
BIBLIOGRAPHY
-65PART I I
BIBLIOGRAPHY
1*
W i e l a n d and H o r n e r :
Ann. 5 3 6 , 89 ( 1 9 3 8 )
2.
P a t t e r s o n : J .A .C .S . 50, 3082 (1928)
3.
Sandme ye r: Z e i t s c h r . f u r F a r b e n c h e m i e , I I ,
4.
Ger. 1 23, 8 8 7 .
5.
Sandme ye r: H e l v . Chim. A c t a ,
6.
U .S. 1,792,170
7.
G a l l o w a y : Chem. R e v i e w s ,
8.
B o r s c h e : B e r . 5 7 , 1149 ( 1 9 2 4 )
9.
M arv el and H i e r s :
129
125, 916.
II,
234 ( 1 9 1 9 )
17, 341 (193 5)
"Organic S y n t h e s e s " C o l l e c t e d V o l . I , 32 1
10.
S e i d e and T i t o v : B e r . 6 9 , 18 84 ( 1 9 3 6 )
11.
S e id e : Ber. 59,
12.
He pn er : M o n a t s c h . 2 7 , 1 0 4 5 ( 1 9 0 6 )
13.
L e l l m a n and S c h m i d t : B e r . 2 0 , 3 1 5 4 ( 1 8 8 7 )
14.
B o g e r t and R o b i n s o n : J . Org. Chem. I ,
15.
Kaufman and R a d o s e v i c : B e r . 4 2 ,
16.
Marckwald: Ann. 2 7 4 , 3 3 1 ( 1 8 9 3 )
17.
P auling:
18.
F ieser:
19.
F r i e d m a n : T h e s i s - N e w York U n i v e r s i t y - 1 9 3 8
20.
W i l l g e r o d t and J a b l o n s l c l : B e r . 3 3 ,
21.
B orsch e: B er . 42 , 4072 (1909)
22.
L ind ner: Monatsch. 4 2 , 421 (1922)
23.
B o r s c h e and J a c o b s : B e r . 4 7 , 35 4 ( 1 9 1 4 )
2465 (1 9 2 6 )
65,
(1936)
2612 ( 1 9 0 9 )
"Gilman’ s T r e a t i s e " 1 8 8 0 .
J . A . C . S . 5 7 , 145 9 ( 1 9 3 5 )
2926 (19 0 0 )
-66SUMIvlAKY
PART I
An im pro ve d method o f p r e p a r a t i o n o f 5 - ,
6-, 7 -,
and 8 - a m i n o - q u i n o l i n e a s w e l l a s t h e p r e p a r a t i o n o f c e r ­
tain
s u l f a n i l a m i d o d e r i v a t i v e s o f p y r i d i n e and q u i n o l i n e
a m in e s i s
described.
PART I I
The Sandmeyer i s a t i n
s y n t h e s i s as a p p l i e d t o c e r ­
t a i n a m i n o p y r i d i n e s and a m i n o q u i n o l i n e s h a s be e n i n ­
v estigated .
Of t h e s e ,
2-am inopyridine, 2 ,6 -d ia m in o p y rid in e,
and 8 - a r a i n o q u i n o l i n e f a i l e d t o fo r m i s o n i t r o s o a c e t y l
d erivatives.
Although 5 -a m in o q u in o lin e , 6 -a m in o q u in o lin e ,
and 3 - a m i n o p y r i d i n e form i s o n i t r o s o a c e t y l d e r i v a t i v e s ,
r i n g c l o s u r e c o u l d o n l y be e f f e c t e d in t h e c a s e 6 f 6 - i s o n itro so a cety la m in o q u in o lin e.
l,2 -D ik e to -3 -p y r r o lo [3,2-f]]
q u i n o l i n e was s y n t h e s i z e d
and c h a r a c t e r i z e d by f o r m a t i o n o f i t s
oxime and t h e bar ium
s a l t of ( 6 -a m in o -5 - q u in o ly l-) g ly o x y lic acid*
The a p p l i c a ­
tio n o f the F f i t z i n g e r r e a c tio n t o 1 , 2 -d ik e to - 3 - p y r r o l o
[3,2-f|
q u inolin e
i s also describ ed .
1.1HHAKT
i s . V . U ntv .'
rr';.-7
;K -'x
T H E GRIGNARD REACTIO N ON ALP.HAPIN E N E OXIDE
VI
BY KENNETH L. RUSSfiLL
'
, -
V
' ■'
-,
■
V
‘’ ' ‘
’ jfA i';.v'’r‘
. |U
T H IS TH ESIS HAS B E E N ACCEPTED BY T H E. QRADUATE S C H O fe ;*»>
O r N EW YORK UNIVERSITY IN PARTIAL FULFILLM EN T O F f V
T H E REQUIREM ENTS FOR T H E U E Q R E E O F
• <
D O C lrbk O F PH ILO SO PH Y
■
C
/
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A y -^ S h '
...
t
f '
V Aj;
-.
v’ly' '
•,
r '4
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--
NEW YORK, N. Y.
1936
[R eprinted from th e Jo u rn al of th e American Chem ical Society, 58, 201 (1838).]
;•> ;J \
iV' ‘,'v
[R eprint from th e Journal of th e A merican Chemical Society, 58, 201 (1936).]
[C o n t r i b u t io n p r o m t h e C h e m i c a l L a b o r a t o r y o p t h e W a s h in g t o n S q u a r e C o l l e g e o p N e w Y o r k U n i v e r s it y ]
The Grignard Reaction on Alpha-Pinene Oxide
By
John
J.
R it t e r a n d K e n n e t h
The action of Grignard reagents upon alphapinene oxide (I) has been investigated recently by
Prileshaev and Vershuk.2 These authors stated
th at the reaction proceeds in a complicated man­
ner with methyl, ethyl and isopropylmagnesium
halides with the formation in each case of gaseous
products and an alcohol (IV). Isobutyl and
phenylmagnesium halides, however, appeared to
act normally to form saturated alcohols (V).
We have repeated and extended this work, and
have now secured evidence which indicates that
the alcohol formed from alpha-pinene oxide and
methylmagnesium iodide is methylcampbolenol
(III). The newly assigned structure is based
upon the fact th at campholenic aldehyde (II),
prepared by isomerization of alpha-pinene oxide
with anhydrous zinc bromide according to the
method of A. Arbuzov’ reacts with methylmag­
nesium iodide to yield methylcampholenol (III)
(1) T his paper Is based upon a portion of th e D issertation sub­
m itted by M r. Russell to th e G rad u ate School of New York Uni­
versity in December, 1935, in partial fulfilm ent of th e requirem ents
for th e Ph.D . degree.
(2) Prileshaev and V ershuk, J . Russ. Phys.-Chem. Soc., 61, 473
(1929).
(3) A. Arbuxov, Ber., 88, 1430-1435 (1035).
L.
R u ssell1
identical with th at obtainable directly from alphapinene oxide by the action of the same reagent.
The products of the action of a series of Grignard
reagents upon alpha-pitteriS tfxide seem to be an­
alogous to methylcampholenol, and probably
possess the same type of structure.
I t has been found recently by Arbuzov3 th at
the Reformatzky reaction upon alpha-pinene ox­
ide likewise involves a simultaneous isomeriza­
tion to campholenic aldehyde (II). It may be
noted also th at products of ring isomerization in
Grignard reactions with other cyclic olefin ox­
ides have been observed occasionally.4
The volumes of gases evolved in these reactions
were found to diminish greatly, and the yield of
alcohol, to increase correspondingly, when the re­
action is allowed to take place for a longer period
and a t an elevated temperature. Even so, not
inconsiderable amounts of gas are obtained, al­
though the quantity is small in comparison with
the yield of alcohol. The gases apparently arise
(4)
Bed os, Compt. rend., 189, 255 (1929); G od ch o t and Conquil,
ibid., 186, 375, 954 (1928); Godchot, Conquil a n d Bedos, Bull. soc.
chim., 48, 521 (1928); Vavon and M etchavetch, Compt. rend., 186,
702 (1928).
292
J ohn
J.
R it t e r
and
K
enneth
L.
R u ssell
Vol. 58
over anhydrous sodium sulfate, and distilled under re­
duced pressure after removal of the chloroform on the
water-bath: yield 70-75% ; b. p. (12 mm.) 70-71°;
rf20, 0.9627; «“ d 1.4709; [«]25d + 65.3. This procedure is
substantially the same as th at of Prilezhaev.*
Methylcampholenol.—To magnesium (6.5
CH;
R
g., 0.27 mole) and ether (30 cc.), a solution
I
of 38 g. (0.27 mole) of methyl iodide in
H
C
30 cc. of ether is added, following the usual
0=C
HC
CH
technique of Grignard reagent preparations.
OH
ZnBr,
An additional 60 cc. of ether is added shortly
CHjCCH,
after the reaction has started. a-Pinene
oxide (35 g., 0.23 mole) dissolved in 35 cc.
H ,C \
H,CX
CH,
CH,
of ether is then added during one and onehalf hours. About 1200 cc. of methane is
CH
H
evolved during this operation. The re­
CH,—C—CH,
(II)
action mixture is then refluxed for one hour,
H
CH,
after which 125 cc. of benzene is added, and
(IV)
the ether distilled off (until the vapor tem ­
perature reaches 70°). The reaction is
HCX
^X C H
completed by an additional six hours’ reCH,MgI,
H ,0
fluxing of the benzene solution. Hydroly­
C H .dC H ,
sis of the addition product by dropwise
H ,C
addition of about 20 cc. of water releases
/CH,
an additional 150 cc. of methane. The pre­
cipitated magnesium hydroxide is dissolved
CH,
H
by addition of 500 cc. of saturated am ­
R\
/C H ,
(I)
CH, C.
monium chloride solution, the benzene layer
I
separated, washed, dried over anhydrous
9\
HOHC
CH
H O H C/' CHzMJH
sodium sulfate, and freed of benzene by dis­
CHjM gl,
tillation from the steam-bath. Distillation
CH,C
CH,CCH,
H ,0
of the remaining material at 4 mm. yields
,-CH,
C H,
H,C
H ,C
29 g. of the alcohol; b. p. 84-86°. Redis­
tillation a t 4 mm. yields 27 g. with the
following constants; b. p. (4 mm.) 82-83°;
H
H
(12 mm.) 107-108°; d u , 0.9162; » 2° d
(V)
(III)
1.4755;- » “ d 1.4770; [ « ] 22d -4 .0 ° ; M R
(calcd.) 51.75; found, 51.73.
Experimental
Anal. Calcd. for CnHsoO: C, 78.49; H, 11.98. Found:
Perbenzoic Arid.—T h isw a i prepared by the method of
C, 78.36, 78.01; H , 12.25, 11.91.
B. T. Brooks.* The-yield obtained (91% ) equaled th at
Prilezhaev reported: b. p. (13 mm.) 109-110°; d*‘ii
reported by Brooks;when the alternative procedure de­
0.9275; »>*d 1.4769; [ « ] 22d +7.90° (from a 1-rotatory
scribed in th at publication was followed.
a-pinene oxide). The use of benzene as solvent in the
Pinene.—a-Pinene (Hercules Powder Company) was
foregoing procedure was suggested by the method of E. E.
refluxed over sodium for one hour and then distilled, the
fraction boiling a t 155-156° (corr.) being collected sepa­ Dreger.7
Determination of the Double Bond in Methylcampho­
rately and used for the following experiments. ( a ] 22D
varied between + 2 4 and + 2 6 ° for a number of prepara­ lenol.— (a) 4.990 g. of alcohol reacted with 3.67 g. of
perbenzoic acid, indicating 0.92 double bond per molecule,
tions.
(b) 0.2000 g. of the alcohol reacted with 0.2900 g. of
Alpha-Pinene Oxide.—a-Pinene ( [ « ) 22d 25.2°) is added
to a 10% excess over one mole of perbenzoic acid dissolved iodine, or the equivalent of 0.966 double bond per molecule.
Analysis of the Gaseous Reaction Products.—These were
in chloroform (15 g„ 100 cc.). The addition is carried
out very slowly (one hour) a t 0° with constant mechanical analyzed by the ordinary procedure in each case, for which
stirring, care being taken to avoid a rise in tem perature of the details are omitted.
Methylcampholenone (a-Campholenic acid methyl
more than five degrees. The reaction mixture is kept a t
0-5° for three days, when the amount of unreacted per­ ketone).—To a solution of sodium dichromate hydrate
benzoic acid (determined iodimetrically) corresponds (10 g.), concentrated sulfuric acid (11 g.) and water (80
cc.) contained in a glass-stoppered bottle is added 10 g.
closely to the 10% excess added initially.
of methylcampholenol. The mixture is shaken for oneThe reaction mixture is then extracted with 10% sodium
hydroxide solution to free it of benzoic acid, washed, dried half hour, and then allowed to stand overnight. I t is
partly from the decomposition of unreacted alkylmagnesium halide and partly from side reactions
which have been commonly observed hitherto in
Grignard reactions.
\
JS \
AS
(5) B. T . B rooki and W. B. B r o o k s , T h i s J o u r n a l , SB, 4309
(1933).
(6) Prilezhaev, Ber., 43, 4814 (1909).
(7) E . E. Dreger, ' ‘Organic S ynth eses/’ Coll. Vo). I, John Wiley
and Sons, Inc., New Y ork C ity, 1932, p. 299.
Feb., 1930
T
he
G r ig n a r d R e a c t io n
T able
iI
CiH,
Approx. vol. gas, cc.
Anal, gas (approx.) %
B. p., 4 mm.
d*\
»**D
[a ]« D
M r found
M r calcd.
% C calcd.
% H calcd.
% C found
% H found
Double bond per mol.
1200
90 C,H,
.10 C,H4
88-89
0.9125
1.4740
-2 .9
56.11
56.37
79.04
12.19
78.65
12.28
0.94
o n ck- P i n e n e
I
II
II I
1300
75 C,H»
25 C»He
1000
80 C4H,„
20 C4H»
110-112
0.8987
1.4721
100-101
0.9024
1.4720
- 4 .5
60.96
60.54
79.69
12.24
79.00
12.36
then extracted w ith ether in tw o portions of 40 cc. each,
the ether solution washed w ith water, 5% sodium car­
bonate solution, water again, an d dried over anhydrous
sodium sulfate. After removal of th e ether the ketone (6 g.)
is distilled at 4 m m .: b. p. 73-74° (4 mm.); d**4 0.9214;
nn D 1.4690; semicarbazone, m. p . 175-176° (corr.).
Campholenic Aldehyde.—a-Pinene oxide was isomerized according to the method of Arbuzov:* 40 g. of the
oxide is dissolved in 100 cc. of d ry benzene and 0.5 g. of
anhydrous zinc bromide added. The mixture is heated
on the steam -bath for one and one-half hours. The violent
reaction described by Arbuzov was not noted in this prepa­
ration. The benzene is distilled off from the steam-bath
and the aldehyde distilled from the residue at 12.5 mm.
Twenty-five gram s of product (62.5%) is obtained; b. p.
(12.5 mm.) 83-84°; n l,D 1.4676; semicarbazone, m. p.
138-139° (corr.). Arbuzov* reported: b. p. (12.5 mm.)
83°; n 17D 1.4668; semicarbazone, m. p. 138-139° (corr.).
Grignard Reaction on Campholenic Aldehyde.—Methyl
magnesium iodide in ether, prepared in the usual manner
is treated with 18 g. (one equivalent) of campholenic alde­
hyde, added during one half hour. About 200 cc. of a gas
(probably m ethane) is evolved during the addition of the
aldehyde. T he mixture is refluxed for an additional two
hours, then hydrolyzed by pouring into an ice and water
mixture containing dilute sulfuric acid. The ether layer
is separated, neutralized with 5 % sodium carbonate solu­
tion, dried over anhydrous sodium sulfate, the ether re­
moved, and the product distilled at 4 mm.: b. p. (4 mm.)
293
O x id e
65.52
65.57
79.92
12.38
79.89
12.11
IV
iso-CjHi
1500
60 C4H i»
40 C4H,
106-107
0.8939
1.4715
65.58
65.57
0.94
V
C.HS
None
140-142 (1.3 m m .)
1.0003
1.5308
-5 .7
78.17
78.48
83.43
9.63
83.01
9.59
0.96
82-83°; dn \ 0.9070; n*°D 1.4750. The product is shown
b y oxidation to methylcampholenone to be identical w ith
methylcampholenol obtained directly from a-pinene
oxide: 8 g. of the product yields 5 g. of the ketone, b. p.
(4 m m .) 73-74°; d**< 0.9224; m 1j d 1.4684; semicarbazone,
m . p. 175-176°; mixed melting point with the semicarba­
zone of methyl campholenone described above showed no
depression.
Additional Campholenols.—A few further alcohols in
this series were also prepared by the action of Grignard
reagents upon a-pinene oxide ( [ a ] 2,D 65.2) by the proce­
dure already described, using equimolar amounts of re­
agents in each case. The yields were close to 70%
throughout. Significant data and the physical properties
of th e preparations are given in Table I.
Rem arks.—Preparations I, IV and V were also de­
scribed by Prilezhaev. Preparation I was oxidized to th e
ketone, ethyl campholenone: b. p. (2 mm.) 80-81°;
d n t 0.9246; «**d 1.4720; semicarbazone, m. p. 148-149°
(corr.).
Summary
A series of alcohols obtained by the action of
G rignard reagents upon a-pinene oxide has been
prepared and characterized. The structures of
the alcohols have been shown to be different from
those previously assigned.
N e w Y o r k , N. Y .
R e c e i v e d N o v e m b e r 6, 1935
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