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SYNTHESIS IN THE ISOQUINOLINE SERIES

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University Microfilms
300 North Z eeb R oad
Ann Arbor, Michigan 48106
A Xerox E ducation Com pany
LD3907
.G7
Barrows, R obert S
I
1940
Syntheses i n the i s o q u in o lin e s e r i e s
•33
New Y o r k , 1 9 4 0 .
3 p . 1 . , 7 9 ( i . e . 8 0 ) , c2 3 , 1 2 t y p e w r i t t e n
leav es,
tab les, d iag rs.
29cm .
T h e s i s ( F h . D . ) - New Y o r k u n i v e r s i t y ,
G raduate s c h o o l, 1940.
B ib lio g rap h y : p . 78-79 (i.e.& O )
"Syntheses i n th e i s o q u i n o l i n e s e r i e s .
Abridgem ent o f a t h e s i s . . .
New Y o r k ,
1940": 2 p . l .,1 2 t y p e w r i t t e n l e a v e s a t
end.
A54481
Shelf List
Xerox University Microfilms,
Ann Arbor, Michigan 48106
T H IS D ISSE R TA TIO N HAS BEEN M IC R O F IL M E D E X A C T L Y AS R E C E IV E D .
L ib ra ry
N, Y. UnivJ
SYNTHESES IN THE ISOQUINOLINE SER IES.
A Thesis
subm itted in p a r t i a l f u lf i l l m e n t
of th e r e q u i r e m e n t s f o r th e d eg ree
of D octor o f P h ilo so p h y a t
New Y ork U n i v e r s i t y
by
R o b e r t S . Barrows.
A p ril,
1940.
PLEASE NOTE:
Some pag e s may have
i nd i s t i n e t
Filmed
U n iversity
as
M icrofilm s,
p rin t.
received.
A X e r o x E d u c a t i o n Company
ACKNOWLEDGMENT
The a u t h o r w i s h e s t o e x p r e s s
h is sin cere a p p re c ia tio n for
th e i n t e r e s t and h e l p f u l sug­
g estio n s o ffe re d
by P r o f e s s o r
H . G. L i n d w a l l d u r i n g t h e
course
of t h i s
in v estig atio n .
TABLE
C hapter I .
OF
CONTENTS.
In tro d u ctio n .
!•
P u rp o se of th e R e s e a r c h .
1«
A lk a lo id s of th e I s o q u in o lin e Group.
2.
The S y n t h e s i s o f 1 - S u b s t i t u t e d I s o q u i n o 1
ine s .
C hapter I I .
9
•
D i s c u s s i o n of t h e E x p e r i m e n t a l
P art.
20.
l* M eth y liso q u in o lin e.
20.
Isoquinaldaldehydes.
24.
D e ta ils of the O x id a tio n s.
31.
C o n d e n sa tio n s of I s o q u in a ld a ld e h y d e s .
33.
C hapter I I I .
E xperim ental P a r t .
47.
l-M eth y l-3 ,4 -d ih y d ro iso q u in o lin e •
47.
1-M eth y liso q u in o lin e.
50.
D e riv a tiv e s of 1 -m e th y liso q u in o lin e .
51.
Isoq u in ald ald eh y d e.
53.
Sem icarbazone of is o q u in a ld a ld e h y d e .
56.
Oxime o f i s o q u i n a l d a l d e h y d e .
57.
Phenyl hydrazone of is o q u in a ld a ld e h y d e .
58.
0 ( - N itr o m e th y l- l- is o q u in o lin e M ethanol.
59.
£ -H y d ro x y -^ -l-is o q u in o ly lp ro p io p h e n o n e . 60.
£ - 1 -1 so q u in o ly lacry lo p h en o n e.
61.
3 - ( l - I s o q u i n o l y l ) - l , 5 - d i p h e n y l - l , 5-pentaned io n e.
63.
fl(-P h en y l-l-iso q u in o lin eacry lo n itrile.
64.
«l-P heny l-P -hy droxy -l-isoqu inolineprop io n ic a c id , E thyl e s t e r .
66
.
3-M ethy1 - 6 , 7 -m e th y le n e d io x y is o q u in a ld aldehyde.
67.
Oxime o f 3 - M e t h y l - 6 , 7 - m e t h y l e n e d i o x y isoquinaldaldehyde.
69.
- P h e n y l - ^ - ( 3 - m e t h y 1 - 6 ,7-me t h y l e n e d i o x y l-iso q u in o ly l)-acry lo n itrile.
70.
3 -M eth y l-6 ,7 -d im eth o x y iso q u in ald ald eh y d e. 7 1 .
A ppendix.
72.
Summary.
77.
B ibliog raph y.
78.
-1 -
CHAPTER
INTRODUCTION.
THE PURPOSE OF THE RESEARCH.
The p u r p o s e o f t h i s
r e s e a r c h was t o p r e p a r e
iso ­
q u in a ld a ld e h y d e and s u b s t i t u t e d i s o q u i n a l d a l d e h y d e s .
T hese a l d e h y d e s were t o
be s t u d i e d
in order to lead
t o new m e t h o d s o f s y n t h e s i s o f i s o q u i n o l i n e compounds
w h i c h w o u l d be s i m i l a r i n s t r u c t u r e
ally
to c e r t a i n n a t u r ­
occurring iso q u in o lin e a lk a lo id s .
t h a t co n d en satio n of th e se
ylene
I t was b e l i e v e d
com po und s w i t h a c t i v e m e t h ­
com pou nds s u c h a s p h e n y l a c e t o n i t r i l e
and e t h y l
p h e n y l a c e t a t e w o u l d l e a d t o new com po unds w h i c h m i g h t
be p h y s i o l o g i c a l l y a c t i v e .
A thorough survey of the l i t e r a t u r e
revealed th a t
s u c h i s o q u i n o l i n e a l d e h y d e s w e r e unknown, a n d t h a t
t u r e s of the type a r r i v e d a t
stru c­
by c o n d e n s a t i o n r e a c t i o n s
o f t h e a l d e h y d e w er e a l s o u nknow n .
In o r d e r to p r e p a r e th e groundwork f o r f u r t h e r r e ­
search,
i t was d e c i d i e d t o s t u d y t h e
s y n th e s is of such
a l d e h y d e s , and t o s t u d y t h e c o n d e n s a t i o n s of i s o q u i n a l d ­
aldehyde .
-2 -
ALKALOIDS OF TIffi ISOQUINOLINE GROUP.
Among t h e a l k a l o i d s t h e r e a r e a n u m b e r o f b a s i c
n i t r o g e n co mpounds w h i c h a r e c o n v e n i e n t l y c l a s s i f i e d
a s i s o q u i n o l i n e a l k a l o i d s * The b u l k o f t h e w ork w h i c h
h a s b een done i n th e i s o q u i n o l i n e f i e l d h a s been c o n c e r n ­
ed w i t h t h e c h e m i s t r y o f t h e s e a l k a l o i d s a n d r e l a t e d
p ro d u cts.
Of e s p e c i a l i m p o r t a n c e a r e t h e
opium a l k a l o i d s ,
an d
one a l k a l o i d d e r i v e d f r o m t h e H y d r a s t i s c a n a d e n s i s , known
a s h y d r a s t i n e . L a r g e a m o u n t s o f opium a r e m a n u f a c t u r e d e a c h
y e a r f o r m e d i c i n a l p u r p o s e s ; i n 1933 t h e l e a g u e o f N a t i o n s
e s t i m a t e d t h a t more t h a n two m i l l i o n k i l o g r a m s o f opium
w er e l e g i t i m a t e l y p r e p a r e d .
P a p a v e r i n e P a p a v e r i n e was i s o l a t e d
f r o m opium i n
1 8 4 8 by M e r c k l . A b o u t f o r t y y e a r s l a t e r , G o l d s c h r a i e d t 2
showed by a n e x c e l l e n t a p p l i c a t i o n o f t h e m e t h o d o f o x i ­
d ative
d e g r a d a t i o n t h a t p a p a v e r i n e was t e t r a m e t h o x y - 1 -
benz y l i s o q u i n o l i n e .
A . P i c t e t a n d A. Gams^ c o m p l e t e l y v e r i f i e d G o l d s c h m i e d t s
stru ctu re
by t h e s y n t h e s i s o f p a p a v e r i n e ;
may be shown s c h e m a t i c a l l y a s b e l o w :
0
ii
C l- C
<s>och
0CH3
3
th e ir sy n th esis
CHo
NaHg
I
_q-ch3
ch3
**
ch3- o
ch3- g
I
-CHo
1
-0-CH3
'orCHg
Many o t h e r s y n t h a s e s h a v e b e e n d e v e l o p e d ^ *
P apaverine i s a h y p n o tic ,
b u t i s much w e a k e r i n i t s
a c t i o n th a n m orphine. I n sm all d o ses p ap av erin e causes
n arco sis,
i n l a r g e r d o s e s r e s p i r a t o r y p a r a l y s i s and t e t a ­
n u s . A c c o r d i n g t o H a l e 5 # t h i s d r u g h a s l e s s e f f e c t on t h e
The s t r u c t u r e s o f t h e a l k a l o i d s h a v e b e e n i n v e r t e d
in th is
these
s e c t i o n t o a g r e e w i t h t h e o l d e r method of w r i t i n g
stru ctu res*
I
-4 -
h e a r t m u s c l e s t h a n many o f t h e
o th e r h y p n o tic s . Sm all6
s t a t e s t h a t p a p a v e r i n e h a s an a n t i s p a s m o d i c a c t i o n on
s m o o th m u s c l e a n d i s
used,
ch iefly
in Europe, to r e lie v e
b ro n c h ia l and i n t e s t i n a l spasm s.
L audanosine. N a tu ra lly o c c u rrin g laudanosine i s
d-N -m ethyltetrahydropapaverine. I ts
strated
s t r u c t u r e w as demon­
by t h e r e d u c t i o n o f p a p v e r i n e m e t h o c h l o r i d e w i t h
t i n and h y d r o c h l o r i c a c i d
by P i c t e t a n d A t h a n a s e s c u 7 *
The r a c e m i c m i x t u r e o b t a i n e d by t h i s r e d u c t i o n w as r e ­
s o l v e d and t h e d f e m
found to
be i d e n t i c a l w i t h t h e
n a t u r a l l y o c c u r r i n g l a u d a n o s i n e . The c o m p l e t e
sy n th esis
f o r l a u d a n o s i n e w a s a c c o m p l i s h e d by P i c t e t a n d F l n k e l s t e i n 8 , and i s
of in te re st
sin ce
i t was t h e f i r s t
syn­
th e s is of an iso q u in o lin e a lk a lo id .
I t s sy n th esis is
very s im ila r to t h a t
except th a t 3 ,4 -
of papaverine,
d i h y d r o p a p a v e r i n e was f i r s t
s y n th e s i z e d and th e n reduced
a f t e r m e t h y l a t i o n t o giv e the ra c e m ic l a u d a n o s in e .
L a u d a n o s i n e h a s b e e n shown t o
be f a r more t o x i c t h a n
p a p a v e r i n e , a n d A . B a b e l 9 h a s shown t h a t t h e o n l y a l k a ­
l o i d o c c u r r i n g i n opium w h ich a p p r o a c h e s i t
i s t h e b a i n e . Because o f i t s h i g h t o x i c i t y
p ro p erties,
in toxiocity
the n a r c o tic
i n w hich i t re se m b le s p a p a v e r in e , are n o t
usefu l.
N a rc o tin e . - N arcotine
o c c u r s i n opium,
some s a m p l e s
o f opium c o n t a i n i n g m ore t h a n t e n p e r c e n t . The s t r u c t u r e
h a s b e e n d e t e r m i n e d by r e d u c t i v e h y d r o l y s i s -*-0 a n d o x i d a ­
-5 -
t i v e h y d r o l y s i s ^ ! , and h a s
been confirm ed
by t h e s y n t h e s i s
of F e rk in . and R o b i n s o n ^ .
.0-
HC
C=0
N arco tin e.
S. Frankel-*^ s t a t e s t h a t n a r c o t i n e h a s p h y s i o l o g i c a l
properties
s im ila r to th e b a in e
and m o rp h in e .
the s e n s e s a t f i r s t ,
but t h i s
c o s i s and p a r a l y s i s .
In la rg e doses i t
I t sharpens
i s q u i c k l y f o l l o w e d by n a r ­
p a ra ly z e s the h e a r t
m u s c l e s an d t h e b lo o d p r e s s u r e d r o p s . D e a t h f i n a l l y r e s u l t s
fro m r e s p i r a t o r y p a r a l y s i s .
N a r c e i n e . - N arceine i s
present
l a t e d f r o m opium by P e l l i t i e r
i n o p i u m , and was i s o ­
i n 1 8 3 2 . The s t r u c t u r e
below h a s been a s s i g n e d t o narceine'*-4 :
0-
CH
H o - C ----
-CH.
given
-6 -
F o r a s h o r t t i m e t h e d o u b l e compound o f s o d i u m n a r c e i n a t e a n d s o d i u m s a l i c y l a t e was u s e d u n d e r t h e name
o f na u t 8 p a 8 m i n " . I t h a d a m o r p h i n e - l i k e a c t i o n ,
b u t was
a b o u t one f i f t i e t h a s s t r o n g . The e x t r e m e l y w eak n a r ­
c o t i c e f f e c t o f n a r c e i n e makes i t
a b l e d&ug w i l l
u n lik e ly t h a t any v a lu ­
be o b t a i n e d f r o m i t *
H y d r a s t i n e * - H y d r a s t i n e was f i r s t
i s o l a t e d from th e
H y d r a s t i s c a n a d e n s i s by D u r a n t l S in 1851. I t s . s t r u c t u r e
h a s b e e n e s t a b l i s h e d t h r o u g h t h e w ork o f F r e u n d * ® . eta
o x i d a t i v e h y d r o l y s i s th e m olecule i s
tin in e
s p l i t in to hydras-
a n d o p i a n i c a c i d . On h e a t i n g a l o n e H y d r a s t i n e
g i v e s a s th e n o n - b a s i c p a r t m econin, th e
l a c t o n e o f meco-
n in ic a c id .
CH2 - O
p o
-COOH
-O-CH 3
I
O-CH3
O pianic a c i d .
I /
-CO
-O-CH 3
/
O-CH3
M e c o n in *
The b a s i c p o r t i o n , h y d r a s t i n i n e ,
b asic p o rtio n ,
of n arcotine*
co tarnin e,
It
i s an a n alo g o f the
o b t a i n e d from t h e d e g r a d a t i o n
behaves ch em ically and s p e c t r o s c o p i c a l l y
a s t h o u g h i t e x i s t e d i n t h r e e t a u t o m e r i c f o r m s * Th e c o n ­
stitu tio n
o f h y d r a s t i n i n e h a s b e e n sh ow n by e x h a u s t i v e
m e t h y l a t i o n a n d o x i d a t i o n , a n d h a s b e e n c o n f i r m e d by a
l a r g e number o f s y n t h e s e s .
-ch3
A
H OH
P se u d o base
Q uaternary
base»
u
\
CHO
Im ino a l d e h y d e .
The v a l u e o f h y d r a s t i n i n e
i n r e d u c in g u t e r i n e hemor­
r h a g e s h a s l e d t o a number o f w o rk a b le m ethods of s y n t h e s i s ! ? . These s y n t h e s e s a r e m o d i f i c a t i o n s o f D e c k e r 's ^ ®
method o f s y n t h e s i s i n w h ich fo rm y lh o m o p ip e ro n y la m in e
is su b jected to a B isc h le r-N a p ie ra lsk i
The n o r h y d r a s t i n i n e
tin in e
sa lts
19
rin g closure
t h u s form ed i s c o n c e r t e d to h y d r a s ­
by t h e a c t i o n o f m e t h y l h a l i d e s *
The s t r u c t u r e a s s i g n e d t o h y d r a s t i n e
by p i e c i n g t o ­
g e t h e r t h e d e g r a d a t i o n p r o d u c t s i n t h e m o s t l i k e l y man­
n e r i s g iv e n below . A lth o u g h t h i s
re la te d to
cotic
s t r u c t u r e i s so c l o s e l y
th a t of n a r c o ti n e , h y d ra s tin e
shows no n a r ­
p r o p e r t i e s . The a b s e n c e o f a m e t h o x y l g r o u p i s
e v i d e n t l y the r e a s o n f o r th e la c k of n a r c o tic p r o p e r t i e s
H y d r a s tin e h a s a s t r y c h n i n e - l i k e a c t i o n . I t e f f e c t s the
c e n t r a l nervous system ,
c a u s i n g p a r a l y s i s and t e t a n u s .
-8 -
D e a th e v e n t u a l l y r e s u l t s from p a r a l y s i s o f th e h e a r t .
,CE
C= 0
H ydrastine.
H y d r a s t i n i n e a n d C o t a r n i n e H y d r a s t i n i n e an d c o t a r n i n e r e s u l t fro m t h e o x i d a t i v e h y d r o l y s i s o f h y d r a s t i n e
an d n a r c o t i n e r e s p e c t i v e l y . As m e n t i o n e d a b o v e t h e y a r e
b eliev ed to e x is t in th re e ta u to m e ric form s. C otarnine
h a s t h e same s t r u c t u r e a s h y d r a s t i n i n e e x c e p t t h a t a m e t h o x y l group has been in tr o d u c e d i n t h e
8
p o sitio n .
The p h y s i o l o g i c a l p r o p e r t i e s o f c o t a r n i n e an d h y d r a s ­
tin in e
a r e q u i t e s i m i l a r . They b o th a c t a s s t y p t i c s ,
the hydrochloride of co tarn in e
ph th alate
(S typtol)
and
( S t y p t i c i n ) and l a t e r th e
f o u n d some u s e a s s t y p t i c s .
C o t a r n i n e a n d h y d r a s t i n i n e d o n o t h a v e some o f t h e
u n d e s i r a b l e p r o p e r t i e s of t h e i r p a r e n t c o m p o u n d s . The y
a r e n o t h e a r t p o i s o n s and d o n o t p r o d u c e t e t a n u s . As h a s
been m e n t i o n e d , h y d r a s t i n i n e h a s f o u n d wide use a s a d r u g
f o r red u cin g u te rin e hem orrhages.
-9 -
THE SYNTHESIS OF 1-SUBSTITUTED ISOQUINOLINES.
A s e a r c h o f the l i t e r a t u r e
has re v e a le d th a t there
a r e few m e th o d s f o r t h e s y n t h e s i s o f
The f i r s t
1-alk
y liso q u in o lin es.
s y n t h e s i s i s t h a t due t o B i s c h l e r and N a p i e r a l -
s k i ^ 9 , i n w hich t h e y t r e a t e d N -a c e ty lp h e n y le th y la m in e
w ith z in c c h lo rid e
o f phosphorus p e n to x id e .
(I.)
They u s e d n o
s o lv e n t and th e y i e l d o f l- m e th y l - 3 ,4 - d i h y d r o i s o q u i n o l i n e
(II.)
warn v e r y p o o r .
II.
I
T h i s m e t h o d was i m p r o v e d by P i c t e t a n d K a y s 2 0 who r a n
the r e a c t i o n
i n t o l u e n e s o l u t i o n and r e c o v e r e d th e d i ­
h y d r o b a s e i n 25 t o 30 % y i e l d . P i c t e t a n d Kay , h o w e v e r ,
worked w i t h v e r y s m a l l q u a n t i t i e s ,
s t a r t i n g w i t h one o r
tw o g r a m s o f t h e N - a c e t y l p h e n y l e t h y l a m i n e .
D e c k e r and c o - ^ o r k e r s l 8 s t u d i e d t h i s r i n g c lo su re
q u ite th o ro u g h ly w ith re s p e c t to th e c lo s in g of the rin g
to give
su b stitu ted
i s o q u i n o l i n e s . They worked w i t h 3 , 4 -
m e th y le n e d io x y p h e n y le th y la m in e s and o b t a in e d
and t e t r a h y d r o d e r i v a t i v e s . D uring th e
both d ih y d ro
course of t h i s
-1 0 -
w o r k t h e y o b s e r v e d t h a t t h i s r i n g c l o s u r e was much e a s i e r
fo r su b stitu ted
compounds t h a n i t w a s f o r co m p o u n d s w h i c h
underwent r in g c lo s u re to give
sim ple i s o q u i n o l i n e s . Decker
found t h a t p h o s p h o ru s o x y c h l o r id e was an e f f i c i e n t
rin g
c lo sin g agent fo r N -acety l-3 ,4 -raeth y len ed io x y p h en y leth y la m in e , and t h a t
benzene,
t o l u e n e , and x y len e c o u ld
be s a t i s ­
f a c to r ily u tiliz e d as so lv en ts.
D ecker and B ecker have a l s o
shown t h a t t e t r a h y d r o i s o -
q u i n o l i n e s may be s y n t h e s i z e d e a s i l y f r o m s u b s t i t u t e d p h e n y l e t h y l a m i n e s . T he y s y n t h e s i z e d n o r h y d r a s t i n e
by c o n d e n s i n g
hom opiperonylam ine w ith form aldehyde i n th e p re s e n c e o f
h y d ro ch lo ric acid
su lted
on a s t e a m b a t h . The n o r h y d r a s t i n i n e r e ­
i n n e a r l y 85 % y i e l d s .
HC1
^
0
° -v \/
N orh y d rastin in e.
S c h o p f an d B a y e r l e ^ h av e s y n t h e s i z e d l - m e t h y l - 6 , 7 dihy drox y-1 , 2 , 3 , 4 -te tra h y d ro iso q u in o lin e
by a m o d i f i c a t i o n
o f t h e D e c k e r s y n t h e s i s . The h y d r o b r o m i d e o f 3 , 4 - d i h y d r o x y p h e n y l e t h y l a m i n e was t r e a t e d w i t h a n a q u e o u s s o l u t i o n o f
a c e ta ld e h y d e and allow ed t o s ta n d f o r t h r e e d a y s . A f t e r
■
-1 1 -
e v a p o r a t i o n a n 83 % y i e l d o f t h e t e t r a h y d r o i s o q u i n o l i n e
was o b t a i n e d *
The f i r s t m e t h o d f o r t h e p r e p a r a t i o n o f 1 - r a e t h y l i s o quinoline
was r e p o r t e d
by K r a u s 2 2 who o b t a i n e d v e r y s m a l l
a m o u n t s by z i n c d u s t d i s t i l l a t i o n
of papaveroline
(III.)
H0H0CH2
/ \
-OH
OH
III.
P o m e r a n z was t h e f i r s t
stitu te d
worker t o s y n th e s iz e t h i s sub1)
h e t e r o c y c l e . Pom eranz a c c o m p lis h e d h i s s y n t h e s i s
by r e f l u x i n g e q u a l p a r t s
of a c e to p h e n o n e and a m in o a c e ta l
w ith th re e
of s u l f u r i c a c i d . T his s y n th e s is
to fo u r p a r ts
may be o u t l i n e d a s b e l o w :
^
ch5
I
YC=£)
/ 0 - C 2 H5
NH2 -CH2-CH
h2so4
cS
C 2 H5-0*CH -0C 2 H5
-1 3
(HSO4 ) “
NaOH
S te a m
d istill
F i c t e t a n d Gams^^ h a v e p r e p a r e d
1-m
eth y liso q u in o lin e
by a B i s c h l e r - N a p i e r a l s k i t y p e o f r i n g c l o s u r e
am inoraethylphenyl m ethanol (IV .)
on N - a c e t y l -
u sin g xylene as th e
solven t
an d p h o s p h o r u s p e n t o x i d e a s t h e c o n d e n s i n g a g e n t . T h i s r e ­
a c t i o n p r o c e e d s i n r a t h e r good y i e l d s ,
but th e N - a c e t y l -
am inom ethylphenyl m ethanol i s d i f f i c u l t to o b t a i n .
0
IV.
A v a r i e t y o f methods have been used i n a t t e m p t i n g t h e
s y n t h e s i s of N <-acetylam inom ethylphenyl m e th a n o l. P i c t e t and
Gams p r e p a r e d t h e h y d r o c h l o r i d e o f '■ l - a m in o a c e t o p h e n o n e
by
r e d u c t i o n of iso n itro s o a c e to p h e n o n e w ith stan n o u s c h l o r id e
and h y d r o c h l o r i c a c i d . A c e t y l a t i o n o f t h e amino k e t o n e an d
r e d u c t i o n w i t h s o d iu m amalgam g a v e t h e d e s i r e d c a r b i n o l .
0
0
NaOCnH,
isoam yl n i t r i t e
(C laisen
-1 3
0
J
-CH NOH
II
-C-CH2 NH2 .HC1
SnClg
HC1
H2S
a s the t i n
doable s a l t .
0
i 0
H
,C.-CH2 -NH2 .HC1
J
NaHC0 3
(CH3 C 0 ) 20
II
-ch 2 -nh-c-ch3
Na-Hg
0
H OH
||
—V-CHg-NH-C -CH3
S l o t t a an d H e l l e r 2 5 h a v e r e d u c e d a m i n o a c e t o p h e n o n e
hydrochloride,
obtained
by a d i f ^ e n t m e t h o d , w i t h p a l ­
l a d i u m . L a rg e am ounts o f p a l l a d i u m were used and th e
y i e l d s w er e l o w , a b o u t 26 % . S l o t t a a n d H e l l e r o b t a i n e d
th e am inoacetophenone h y d r o c h lo r id e
by t r e a t i n g
bromo -
acetophenone w ith hexam ethylene te tra ra in e a c c o rd in g to
t h e m ethod o f M a n n i c h a n d H a h n 2 5 #
0
0
^ x _ L •CH2 Br
Hexame t h y l e n e .
tetram ine
HCJ?’
II
!-CH2 -NH2 .HCl
Pd
HC1
O th er methods have been r e p o r t e d
i n the l i t e r a t u r e
f o r t h e p r e p a r a t i o n of p h e n y l e t h a n o l a m i n e . W olfheim27
an d Rupe28 a t t e m p t e d th e r e d u c t i o n o f m a n d e l o n i t r i l e w i t h
s o d i u m a m a lg a m . The m e t h o d i s l o n g a n d l a b o r i o u s a n d g i v e s
v e r y p o o r y i e l d s . K i n d l e r a n d P e s c h k e ^ 9 r e p o r t t h a t man­
d e l o n i t r i l e may be r e d u c e d c a t a l y t i c a l l y ,
but t h a t phenyl-
ethylam ine i s o b ta in e d in s te a d of th e d e s ire d ethanolam ine.
K i n d l e r and P e s c h k e 2 9 have d e v e l o p e d a v e r y n i c e method
f o r th e s y n t h e s i s o f p h e n y le th a n o la m in e and s u b s t i t u t e d
phenylethanolam ines,
but t h e i r m ethod r e q u i r e s an a p p a r a t u s
w hich i s n o t a v a i l a b l e
i n m o s t l a b o r a t o r i e s . Th ey p o i n t o u t
t h a t although the m a n d e lo n itrile
c a n n o t be e a s i l y r e d a c e d ,
t h e k e t o a c t i v a t e d co m p o u n d s may be r e d u c e d , Af t e r t h e
r e d u c tio n of th e cyano- o r n i t r o s o - group, the carbonyl
g r o u p w i l l r e d u c e . T h e i r a p p a r a t u s i s so d e s i g n e d t h a t
a s o lu t i o n of th e m a t e r i a l to
be r e d u c e d i s d r o p p e d o n t o
a s u sp e n s io n of th e c a t a l y s t
in th e presence o f hydrogen.
I n t h i s way t h e r e d u c t i o n i s
i n s t a n t a e n e o u s and th e a u th o rs
c l a i m t h a t v e r y good y i e l d s a r e o b t a i n e d .
Rosenmund^O i n 1 9 1 2 r e p o r t e d t h e r e d u c t i o n o f * - p h e n y l - / *
- n i t r o e t h a n o l w i t h s o d i u m am a lg a m a n d i s o l a t e d t h e e t h a n o l ­
am in e a s a b e n z o y l d e r i v a t i v e . H i s y i e l d s w e r e e x c e e d i n g l y
p o o r. A lex
N a g a i^ l
o b ta in e d a p a t e n t fo r the r e d u c tio n
o f ^ - p h e n y l- ^ - n itr o e th a n o l in 1935,
but did n o t d isc lo s e
th e c o n d i t i o n s under w hich th e r e d u c t i o n to o k p la c e ex­
c e p t t h a t i t w as done w i t h i r o n d u s t . L a t e r , i n 1 9 3 6 , N a g a i 3 8
reduced the p ro d u ct ob tain ed
by c o n d e n s a t i o n o f p i p e r o -
n a l w i t h n i t r o m e t h a n * . Once a c ' a i n t h e y i e l d and d e t a i l s
w er e n o t a v a i l a b l e .
N itroraethane h a s
been cond ensed w ith a r y l a ld e h y d e s
by a n u m b e r o f w o r k e r s 3 3 , a n d t h e c o n d e n s a t i o n p r o c e e d s
n ic e ly giving e i t h e r a n itro s ty re n e
or an a l d o l p r o d u c t
d e p e n d i n g on w h e t h e r t h e d e c o m p o s i t i o n o f t h e
s odiu m s a l t
i s accom plished w ith s u l f u r i c a c id or a c e tic a c id .
The d e h y d r o g e n a t i o n of 3 , 4 - d i h y d r o i s o q u i n o l i n e s w as
first
a c c o m p l i s h e d by P i c t e t and K a y ^ ° who o x i d i z e d 1 -
p h e n y l - 3 , 4 - d i h y d r o i s o q u i n o l i n e an d l - f e e n z y l - 3 , 4 - d i h y d r o i s o q u i n o l i n e w ith p o ta ss iu m perm anganate in the p re s e n c e
of d ilu te
and
1
s u l f u r i c a c i d . P i c t e t a n d Kay o b t a i n e d 1 - p h e n y l
-benzylisoquinoline
i n t h i s way i n a b o u t 80 % y i e l d s .
S p a th and c o - w o r k e r s 3 4 *3 3 have d e h y d ro g e n a te d 1 - a l k y l 3 f 4 - d i h y d r o i s o q u i n o l i n e s an d s u b s t i t u t e d
h y d ro is o q u in o lin e s w ith palladium
were f o r c e d t o p u r i f y
l-a lk y l-3 ,4 -d i­
b l a c k on a s b e s t o s . Th ey
the i s o q u i n o l i n e s c a r e f u l l y
before
u s e a n d c o u l d w ork w i t h o n l y s m a l l a m o u n t s . T h i s m e t h o d
o f d e h y d r o g e n a t i o n w as e x t e n d e d t o t e t r a h y d r o d e r i v a t i v e s
by R e i c h e r t a n d H o f f m a n 3 3 .
B ergstrom and M c A l l i s t e r 3 7 p o s t u l a t e
q uinolines,
u nreactive
rin g
that iso q u in o lin e s,
an d p y r i d i n e s a r e a l d e h y d e d e r i v a t i v e s a n d a r e
o n ly because of th e extrem e s t a b i l i t y
s y s t e m s . Th ey b e l i e v e , t h e r e f o r e ,
of the
th a t these h e te ro c y c le s
16-
s h o u l d ad d one mole o f G r i g n a r d r e a g e n t a c r o s s t h e d o u b l e
bond b e t w e e n c a r b o n a n d n i t r o g e n *
In su p p o rt of t h e i r th e o ry
t h e y h a v e f o u n d t h a t s u c h r e a c t i o n s do t a k e p l a c e i n a m a n n e r
s i m i l a r t o a d d i t i o n t o c a r b o n y l g r o u p s f t h e new c a r b o n g o e s
t o c a r b o n and t h e m a g n e s iu m a d d s t o n i t r o g e n . I n s u c h a
manner, using i s o q u in o lin e , e t h y l
b r o m i d e , an d e x c e s s mag­
n e s i u m t h e y h av e o b t a i n e d g o o d y i e l d s o f l - e t h y l i s o q u i n o lin e.
T h e i r r e a c t i o n was r u n i n e t h e r i n a bomb w h i c h was
h e a t e d t o 1500 u n d e r a n a t m o s p h e r e o f n i t r o g e n . A s i m i l a r
s e r i e s o f r e a c t i o n s was c a r r i e d o u t t o p r e p a r e
other is o ­
q u i n o l i n e d e r i v a t i v e s , a s w e l l a s p y r i d f i n e and q u i n o l i n e
compounds.
ff. D a v i e s , J . E . K e f f o r d ,
th esized
1
-m eth y liso q u in o lin e
and J . L . 0 sb o rn e 3 8 have sy n ­
by a c o m p l e t e l y new m e t h o d *
T hey t r e a t e d t r a n s - W - b r o m o - o - c y a n o s t y r e n e w i t h a n e x c e s s
o f t h e G r i g n a r d r e a g e n t . When t h e
p relim in ary r e a c tio n
w a s c o m p l e t e d , t h e r e s i d u e w as h e a t e d f r o m
the in term ed iate
100
° to
200
°»
compound l o s t m a g n e s i u m h a l o g e n b r o m i d e
a n d t h e 1 - s u b s t i t u t e d i s o q u i n o l i n e was f o r m e d . The o v e r ­
a l l y ie ld rep o tted
by D a v i e s a n d c o - w o r k e r s was a b o u t
13 %. They b e l i e v e d t h a t t h e r e a c t i o n f o l l o w e d t h e c o a r s e :
ou tlined
below:
f 3
^ \-C N
</ x N-C=NMgX
MgXCHjiy.
J-CH-CHBr
E ther
100-20Q1
---------------
-CH-CHBr
-1 7
B r u c k n e r a n d B r u c k n e r a n d K r a m li^ ® * ^ ® h a v e d e v e l o p e d
a m ethod o f s y n t h e s i s f o r l , 3 - d i m e t h y l - 6 , 7 - m e t h y l e n e d i o x y i s o q u i n o l i n e and l ,3 - d i m e t h y l - 6 , 7 - d i m e t h o x y i s o q u in o l i n e . The m e t h o d o f s y n t h e s i s
o f t h e s e two i s o q u i n o l i n e s
is n e a rly i d e n t i c a l except t h a t f o r the f i r s t
t h e s t a r t i n g c o m p o u n d , and f o r t h e
iso safro le
is
second m ethyl iso e u g e -
n o l * The c o u r s e o f t h e r e a c t i o n w i l l
be o u t l i n e d h e r e f o r t h e
i s o q u i n o l i n e d e r i v e d from i s o s a f r o l e *
Iso safro le
is
t r e a t e d w i t h n i t r o u s a n h y d r id e which
i s g enerated in the r e a c tio n m ixture
by d r o p p i n g d i l u t e
su lfu ric
z e r o d e g r e e s . The
a c i d o n t o s o d iu m n i t r i t e
at
n i t r o u s anhydride adds a c r o s s th e double
b o n d . NO g o e s
t o t h e c a r b o n a d j a c e n t t o t h e r i n g a n d N0 £ g o e s t o t h e
c a r b o n f u r t h e s t away f r o m t h e
safro le-lJ-n itro site
r i n g so a s t o f o r m i s o -
( V . ) . The p s e u d o n i t r o s i t e
tr e a t e d w ith a c e t i c anhydride
i s then
in the presence of a l i t t l e
s u l f u r i c a c i d o r p h o s p h o r i c a c i d . The a c e t a t a ( V I . ) w h i c h
resu lts
type
i s th e n e l e c t r o l y t i c a l l y r e d u c e d . A ccording to the
of c a th o d e w hich i s u se d e i t h e r a hydroxylam ine o r
18-
a n a m in e may r e s u l t .
I f t h e c a t h o d e i s made o f ita-
pure l e a d the h y d ro x y la m in e
but i f th e c a th o d e
is
obtained e x c lu s iv e ly ,
i s pure l e a d ,
or plated
lead th e
r e a c t i o n p r o c e e d s f u r t h e r t o g i v e t h e d e s i r e d amine
(VIII.).
/
o-
CHo
N 2 0 ,^
X o-
0
-
0
-\ y \ \
CH2
c h ^ c h -c h 3
NO N0 2
I
CH-CH-CH3
0
CHj
X
-r^N
o - 1'.
N jJ H -(jH -C H 3
•zHC-CO NH2
\
VIII.
nc h - c h - c h 3
3 HC—0 0
o-X X
-C H -C H 3
T 1
0 NHOH
3 HC-C0
(CH3 CO) pO
H2 SO4
19-
The a m i n e i t s e l f i s g e n e r a l l y n o t i s o l a t e d ,
but the
r e d u c t i o n p r o d u c t i s t r e a t e d w i t h s o d iu m c a r b o n a t e
a c e t y l group r e a r r a n g e s ,
and t h e
g o in g from th e h y d r o x y l g ro u p
t o t h e am ino g r o u p . T h i s r e a r r a n g e m e n t may be r e v e r s e d
t r e a t i n g t h e N - a c e t y l am in e w i t h h y d r o g e n c h l o r i d e
by
in
m ethyl a l c o h o l .
0
- / \
/
NaipC O3
NH2 .HC1 — - — y
I
CH3 0 H
CH-CH-CH3
HC1
ch2
0-
0
/
-
4 ?NH
ch2
^CH-CHs
A
H OH
OC-CH3
0
The N - a c e t y l am ine i s t n e n r i n g c l o s e d i n much t h e
same m anner a s o t h e r r i n g c l o s u r e s w h i c h hav e
been d i s ­
c u s s e d f o r 1 - m e t h y l i s o q u i n o l i n e s . The c o n d i t i o n s , h o w e v e r ,
f o r t h e r i n g c l o s u r e a r e much m i l d e r and t h e y i e l d s
Phosphorus o x y chloride
in chloroform
clo sin g agent.
CH3
1 3
0 =C
0CH2
V
A
NH
POC1
,CH-CH3 CHCI 3
A
H OH
is
b etter,
used a s th e r i n g
-2 0 -
CHAPTER I I .
DISCUSSION OF THE EXPERIMENTAL PART.
1-M eth y liso q u in o lin e.of p re p a ra tio n of
1-m
B e f o r e a n a d e q u a t e m e th o d o f
e t h y l i s o q u i n o l i n e was f o u n d ,
s i d e r a b l e amount o f work w i t h n e g a t i v e
a con­
r e s u l t was d o n e .
T h is work h a s been sum m arized i n a n a p p e n d i x t o t h i s t h e s i s .
The m e t h o d f i n a l l y a d o p t e d f o r t h e s y n t h e s i s o f 1 - m e t h y l ­
i s o q u i n o l i n e was a m o d i f i c a t i o n o f a m e t h o d u s e d by S p a t h ^ *
P henylethylam ine, obtained
phenyl a c e t o n i t r i l e
by t h e c a t a l y t i c
in the presence
r e d u c tio n of
o f R a n e y n i c k e l and
h y d r o g e n ( A d k i n s ^ ) , was a c e t y l a t e d w i t h a c e t i c a n h y d r i d e
t o g i v e N - a c e t y l p h e n y l e t h y l a m i n e . S i n c e S p a t h an d h i s w o r ­
k e r s had d e a l t w ith sm all q u a n t i t i e s i n p r e p a r i n g
1-m ethyl-
3 , 4 - d i h y d r o i s o q u i n o l i n e , i t was f e l t w i s e t o s t u d y t h e r i n g
closure
i n o rd e r to determ in e the
b e s t p ro c e d u re f o r the
p r e p a r a t i o n o f l a r g e r am ounts o f l - m e t h y l - 3 , 4 - d i h y d r o i s o q u i n o l i n e . A v a r i e t y of r i n g - c l o s i n g a g e n ts , phosphorus
o x y c h l o r i d e , a lu m in u m c h l o r i d e , a n d p h o s p h o r u s p e n t o x i d e
were u s e d , and a number o f s o l v e n t s
in c lu d in g xylene,
lig ro in ,
c h l o r o f o r m , a n d t e t r a l i n w e r e t r i e d . The r e s u l t s h av e b e e n
summarized i n a t a b l e which a p p e a r s i n th e e x p e r im e n ta l p a r t
o f t h i s p a p e r . The b e s t a g e n t was p h o s p h o r u s p e n t o x i d e , and
th e most d e s i r a b l e
s o l v e n t was f o u n d t o
the h ig h e s t tem perature
be t h e one i n w h i c h
c o u l d be o b t a i n e d ,
th at is ,
te tra lin .
A f t e r a method f o r th e r i n g c l o s u r e o f N - a c e t y l p h e n y l e t h y l a m i n e had been worked o u t , m ethods of d e h y d r o g e n a t i o n
w er e c o n s i d e r e d . The m e t h o d u s e d by S p a t h was n o t c o n s i d e r e d
sa tisfa c to ry
f o r s e v e ra l r e a s o n s . P alladium
u s e d by S p a t h ,
b l a c k w h i c h was
i s q u i t e e x p e n s i v e , an d c o m p a r a t i v e l y l a r g e
am ounts o f i t were u t i l i z e d f o r th e d e h y d r o g e n a t i o n . I n a d ­
d itio n i t
i s n e c e s s a r y , when u s i n g p a l l a d i u m
ca ta ly st,
t o p u r i f y t h e s t a r t i n g compound c a r e f u l l y ,
w ise i m p u r i t i e s ,
b la c k a s the
o th er­
e s p e c i a l l y any f r e e am in e, w i l l p o is o n th e
c a t a l y s t and p r e v e n t s a t i s f a c t o r y d e h y d r o g e n a t i o n . C hem ical
means were f i r s t
su lfu ric
c o n s id e r e d . P otassiu m perm anganate i n d i l u t e
a c id and hydrogen pero x id e
but in n e i t h e r
case could any
1
in d ilu te
a c i d were t r i e d ,
-m eth y liso q u in o lin e
be ob­
tained .
S in c e Raney n i c k e l had proved u s e f u l i n t h i s l a b o r a t o r y
a n d i n many o t h e r s f o r c a t a l y t i c h y d r o g e n a t i o n ,
that i t
tio n .
It
should a l s o
be a n a c t i v e
was f o u n d t h a t
i t was f e l t
c a t a l y s t fo r dehydrogena­
s u c h was t h e c a s e ,
o f Raney n i c k e l t h e d i h y d r o i s o q u i n o l i n e
an d i n t h e p r e s e n c e
underw ent smooth d e ­
h y d r o g e n a t i o n t o 1 - m e t h y l i s o q u i n o l i n e . The c o u r s e o f t h i s
r e a c t i o n c o u l d be e a s i l y f o l l o w e d ,
the m ixture g ra d u a lly in c re a se d
1-m
f o r the
u n t i l the
b o ilin g p o in t of
boiling point of
e t h y l i s o q u i n o l i n e was r e a c h e d .
Some d i f f i c u l t y was e n c o u n t e r e d i n i d e n t i f y i n g t h e
1-m
e th y liso q u in o lin e,
ing p o i n t s
because o f e rro n e o u s ly r e p o r te d m e lt­
o f some o f t h e
n a te ly K efford,
c ry s ta llin e d e riv a tiv e s . F o rtu ­
O s b o r n e , &nd D a v i e s p u b l i s h e d a p a p e r i n
M a rc h o f 1 9 3 9 i n w h i c h t h e y p o i n t e d o u t t h a t t h e m e l t i n g
-2 2 -
p o i n t s of s e v e r a l of th e c r y s t a l l i n e d e r i v a t i v e s r e p o r t e d
p rio r to
1930 w e r # much t o o l o w . A s t u d y o f t h e d e r i v a t i v e s
o f 1 - m e t h y l i s o q u i n o l i n e was m a d e . The c o m p a r i s o n o f t h e
p h y s ic a l p r o p e r tie s of
1
-m e th y liso q u in o lin e
t i v e s to those re p o rte d in the
tab le
literatu re
and i t s d e r i v a ­
i s g i v e n fon a
on t h e n e x t p a g e . M i l l s 4 2 h a s r e p o r t e d a m e l t i n g p o i n t
f o r the m ethiodide
of
1
- m e t h y l i s o q u i n o l i n e which a g r e e s
w i t h t h a t o b t a i n e d i n t h i s r e s e a r c h . The p i c r a t e
in th is
obtained
r e s e a r c h , however, m e lts about f i v e d e g re e s h ig h e r
th a n any p r e v i o u s l y r e p o r t e d p i c r a t e
and a b o u t tw e n ty d e ­
g r e e s h i g h e r th a n the m e ltin g p o i n t s r e p o r t e d p r i o r t o 1930.
N i t r o g e n a n a l y s i s was d o n e on t h e p i c r a t e
and a r e s i d u e d e ­
t e r m i n a t i o n was r u n on t h e c h l o r o p l a t i n a t e . B o t h o f t h e s e
v a lu e s check w ell w ith the t h e o r e t i c a l v a lu e s .
I n o r d e r t o make s u r e o f t h e p u r i t y o f t h e 1 - m e t h y l i s o q u i n o l i n e a t e s t o f i t s h o m o g e n e i t y was m a d e . I n t h i s
a crude
1
s a m p l e o f t h e p i c r a t e was p r e p a r e d ,
-m ethy lisoq uin oline
0 .6
from 0 . 5 g .
g . of crude p i c r a t e
i s o q u i n o l i n e was o b t a i n e d . The m e l t i n g p o i n t
p icrate
was v e r y n e a r l y t h a t o f a p u r i f i e d
ch3
N /V
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-2 4 -
I s o g u in a ld a ld e h y d e s .- A survey of the l i t e r a t u r e
rev eal­
ed t h a t no i s o q u i n o l i n e a ld e h y d e s had e v e r been p r e p a r e d or
i s o l a t e d from n a t u r a l l y o c c u r r i n g p r o d u c t s . A number o f q u i n o ­
l i n e a ld e h y d e s h ad , however,
been p r e p a r e d
by t h e
use o f s e ­
le n iu m d i o x i d e a s a n o x i d i z i n g a g e n t on t h e c o r r e s p o n d i n g
m e t h y l q u i n o l i n e s . H e n z e 4 4 h a s shown t h a t q u i n o l i n e a n d p y r i ­
d i n e d e r i v a t i v e s w h i c h h a v e a c t i v e m e t h y l g r o u p s c a n be o x i ­
d i z e d w i t h s e le n iu m d i o x i d e t o g iv e s m a ll am ounts of thq/corr e s p o n d i n g a l d e h y d e s . W o r k i n g w i t h q u i n a l d i n e and p i c o l i n e
he o b t a i n e d good y i e l d s o f t h e c o r r e s p o n d i n g a c i d s , q u i n a l d i c
a c i d and p i c o l i n i c a c i d ,
an d a s m a l l a m o u n t o f q u i n o l i n e - 2 -
aldehyde.
K w a r t l e r an d L i n d w a l l ^ h a v e shown t h a t l e p i d i n e c a n be
o x id iz e d w ith selenium d io x id e to giv e q u in o lin e - 4 - a ld e h y d e ,
and t h a t
under c a r e f u l l y c o n tr o lle d c o n d itio n s q u in a ld in e
be o x i d i z e d t o q u i n o l i n e - 2 - a l d e h y d e
can
i n g o o d y i e l d s . On t h e
b a s i s o f t h i s w o r k , i t was c o n c l u d e d t h a t
is o q u in o l in e s con­
t a i n i n g a c t i v e m ethyl gro u p s should undergo o x i d a t i o n w ith
selenium d io x id e to give
iso qu ino line aldehydes.
1 - M e t h y l i s o q u i n o l i n e was o x i d i z e d w i t h s e l e n i u m d i o x i d e
by a p r o c e d u r e d i s c u s s e d i n d e t a i l i n t h e f o l l o w i n g s e c t i o n
of t h i s
c h a p t e r . A w h i t e c r y s t a l l i n e p r o d u c t was o b t a i n e d
w h i c h was v o l a t i l e w i t h s t e a m , a n d h a d a l l
istics
of th e c h a r a c t e r ­
o f a n a l d e h y d e . When t r e a t e d w i t h a s a t u r a t e d
o f s o d iu m b i s u l f i t e ,
so lu tio n
i t form ed an a d d i t i o n p r o d u c t , and w i t h
c o l d am m oniacal s i l v e r n i t r a t e
i t produced s i l v e r . D e r iv a tiv e s
-2 5 -
o f th e c a r b o n y l g r o u p were form ed e a s i l y . R e f l u x i n g a s o l u ­
t i o n of th e ald eh y d e i n a w a t e r - a l c o h o l m ix tu re w ith e i t h e r
hydroxylam ine h y d r o c h lo r id e or s e m ic a rb a z id e h y d r o c h lo r id e
g a v e a n oxim e o r s e m i c a r b a z o n e r e s p e c t i v e l y . T h e s e r e a c t i o n s
a f t e r f i v e t o t e n m i n u t e s h e a t i n g o n a s t e a m b a t h w e r e com­
p l e t e . The p h e n y l h y d r a z o n e c o u l d a l s o
be e a s i l y o b t a i n e d
a s l o n g y e l l o w n e e d l e s by a l l o w i n g a h o t s o l u t i o n o f t h e
a ld e h y d e and p h e n y l h y d r a z i n e
in alco h o l to cool.
I n some o f i t . s c h a r a c t e r i s t i c s
quinoline-4-aldehy de
aldehydes,
th is
m elting p o in t
on t ^ «
t h i s compound r e s e m b l e d
and q n i n o l i n e - 2 - a l d e h y d e . L i k e t h e s e
compound i s v o l a t i l e
(about 55°),
w i t h s t e a m , h a s a low
and h a s a n i r r i t a t i n g
effect
s k i n and on t h e mucous membrane o f t h e n o s e . U n l i k e
the q u in o lin e a ld e h y d e s , how ever,
cry stallize
it
sho ws no t e n d a n c y t o
from w a t e r w ith w a t e r o f h y d r a t i o n . E ven th e
sample o b t a i n e d
by s t e a m d i s t i l l a t i o n h a d n o w a t e r o f c r y s ­
tallizatio n .
On t h e
b a s is of i t s
c h e m ic a l p r o p e r t i e s , method o f p r e ­
p a r a t i o n , a n d a n a l y s e s o f t h e p r o d u c t an d i t s d e r i v a t i v e s ,
th is
compound was i d e n t i f i e d
as iso q u in ald ald eh y d e
CHO
II.
(II.).
-2 6 -
The o x i d a t i o n o f 1 , 3 - d i m e t h y l i s o q u i n o l i n e s was n e x t c o n ­
s i d e r e d . On t h e
b a s is of the fo llo w in g d is c u s s io n ,
concluded t h a t the
tia lly
1 -m ethyl
group should o x id iz e p r e f e r e n ­
le a v in g the g -m ethy l group i n t a c t .
The o x i d a t i o n o f
1-m
eth y liso q u in o lin e
oxide to g iv e an aldehyde
i n w h i c h he f o u n d t h a t
1
to give
1-s
m ethyl group in
w ith selenium d i ­
b e a r s o u t t h e work d o n e by M i l l s 4 6
- m e th y lis o q u in o lin e could
sed w ith benzaldehyde in the p resen ce
rid e
i t was
of a l i t t l e
be c o n d e n ­
zinc c h lo ­
t y r y l i s o q u i n o l i n e ; he c o n c l u d e d t h a t
1-m
eth y liso q u in o lin e
the
i s a c t i v e . In the
same
paper M ills d em o n strated t h a t 3 -m e th y lis o q u in o lin e could n o t
be c o n d e n s e d w i t h b e n z a l d e h y d e . A l t h o u g h he u s e d more v i g ­
o r o u s c o n d i t i o n s , he was a b l e t o r e c o v e r no 3 - s t y r y l i s o q u inoline,
the
but could g et n e a r ly q u a n t i t a t i v e
s ta r tin g m a te ria ls . M ills also
iodide of
1
-m eth y liso q u in o lin e
benzaldehyde,
states
re c o v e ry of
t h a t th e raeth-
underwent c o n d e n s a tio n w ith
but th e m eth io d id e of 3 -ra e th y lis o q u in o lin e
d id n o t .
On t h e
b a s is of th e r e a c t i v i t y
q u in o lin es,
be s t a t e d
p y rid in es,
of m ethyl d e r i v a t i v e s
iso q u in o lin es,
th a t ev id en tly
which a t a u t o m e r i c s h i f t
and t h i a z o l e s i t
of
can
o n l y t h o s e m e t h y l co m pounds i n
to give a m ethylene s t r u c t u r e
is
p o s s i b l e w i l l u n d e r g o c o n d e n s a t i o n . The co mmonest c a s e o f
a tau tom eric
sh ift
i s t h a t w hich t a k e s p la c e
i n a system
o f t h r e e a t o m s l i n k e d by one s i n g l e an d on e d o u b l e
N = C — CH3 ^
HN— C = C H 2
bond, e . g .
27-
T his le a d s to the c o n c lu s io n t h a t th e r e
i s a t r u e double
bond b e t w e e n t h e n i t r o g e n a n d a l p h a c a r b o n atom i n s u c h
co m p o u n d s a s q u i n a l d i n e a n d
1-m
eth y liso q u in o lin e,
p o ssib le a tautom eric s h i f t
a s shown f o r
1
making
-m eth y liso q u in o -
lin e.
CH3
h2
11
T h e r a i s n o p o s s i b l i t y off s u c h a t a u t o m e r i c s h i f t
3 -m e th y liso q u in o lin e , since
there
i s no double
in
bond b e t w e e n
t h e n i t r o g e n ato m a n d t h e c a r b o n g r o u p w h i c h b e a r s t h e m e t h y l
group.
H3
The o n l y s t r u c t u r e w h i c h c o u l d be sh ow n f o r 3 - m e t h y l i s o q u i n o l i n e w ith an a c tiv e m ethylene group i s th e
below . In t h i s s t r u c t u r e
one w h i c h i s
th e c o n ju g a te d system o f th e
zene r i n g h a s d i s a p p e a r e d , and t h e s t r u c t u r e
t h e unknown 2 , 3 - n a p h t h a q u i n o n e s .
shown
ben­
is sim ila r to
28-
N
v v ^ CH2
S i m i l a r m e t h y l e n e s t r u c t u r e s c a n be shown f o r a c t i v e
m e th y lq u in o lin e s such as le p id in e
illu strated
an d q u i n a l d i n e , a s i s
b e lo w f o r l e p i d i n e .
CH3
ch2
M i l l s a n d R a p e r 4 ? h a v e shown t h a t s u c h m e t h y l e n e s t r u c ­
t u r e s do e x i s t a n d may be i s o l a t e d
i n some c a s e s . T h e y h a v e
a l s o d e m o n s t r a t e d t h a t t h e m e c h a n i s m of c o n d e n s a t i o n o f
^ -n a p h th a q u in a ld in e e th io d id e w ith aldehydes occurs through
a m e t h y l e n e c o m p o u n d . T h e y sh owed t h a t i n t h e p r e s e n c e
of
p i p e r i d i n e , ^ -n a p h th a q u in a ld in e e th io d id e g iv e s the m e th y l­
ene s t r u c t u r e w hich i s
show i n t h e e q u a t i o n s b e l o w . The
m e t h y l e n e compound was i s o l a t e d a s s u c h a n d c o n d e n s e d w i t h
p - d i m e t h y l a m i n o b e n z a l d e h y d e t o g i v e a n a l l e n e w h i c h w o u ld
a b s t r a c t h y d r i o d i c a c i d from p i p e r i d i n e h y d r i o d i d e .
-2 9 -
/CH3
0=CH■ /
V n
ch3
C 2H5
1
)
= C = -C Ii/
• /CH3
N
sg h 3
JiL
c 2h 5
__ N
H e n z e 4 4 h a s sh own t h a t a n a l k y l g r o u p a t t h e 2 p o s i t i o n
i n t h e q u i n o l i n e m o l e c u l e i s p r e f e r e n t i a l l y o x i d i z e d by
s e l e n i u m d i o x i d e : h e f o u n d t h a t when 2 - e t h y l - 3 - m e t h y l q u i n o -
1
-3 0 -
l i n e was t r e a t e d w i t h a n e x c e s s o f s e l e n i u m d i o x i d e t h e r e
was no o x i d a t i o n o f t h e m e t h y l g r o u p ,
but th e e t h y l group
w as o x i d i z e d t o a c a r b o x y l g r o u p .
/ V
Nv
COOH
x s SeOg
On t h e
of
1-m
b a s is of th e s e p o i n t s ,
eth y liso q u in o lin e,
as w ell a s the
oxidation
i t was c o n c l u d e d t h a t s u b s t i t u t e d
i s o q u i n o l i n e s which c o n t a i n e d a m e th y l g ro u p i n th e
s i t i o n w o u l d be o x i d i z e d by s e l e n i u m d i o x i d e ,
_1
po-
but t h a t th o s e
c o n t a i n i n g a m e t h y l g r o u p i n t h e ,3 p o s i t i o n w o u ld n o t . When
1 , 3 - d i m e t h y 1 - 6 , 7 - r a e t h y l e n e d i o x y i s o q u i n o l i n e was o x i d i z e d by
s e l e n i u m d i o x i d e a m o n o - a l d e h y d e was f o r m e d . T h i s a l d e h y d e
f o r m e d a monoxime w h i c h i s
so lu b le
in e x c e ss acid or base.
I t r e d u c e d ammoniacal s i l v e r n i t r a t e ,
b u t w i t h more d i f f i ­
c u l t y t h a n i s o q u i n a l d a l d e h y d e . On t h e
b a s is o f th e chem ical
p r o p e r t i e s a n d a n a l y s e s o f t h e a l d e h y d e a n d t h e oxime t h i s
com pound was c o n c l u d e d t o
isoquinaldaldehyde
be 3 - m e t h y l - 6 , 7 - m e t h y l e n e d i o x y -
(III.)
■ /V ^ N
■
31-
l , 3 - D i m e t h y l - 6 , 7 - d i m e t h o x y i s o q u i n o l i n e was a l s o o x i ­
d i z e d by s l e n i u m d i o x i d e . I t
m etallic
o x i d i z e d a s w as e x p e c t e d an d
s e l e n i u m c o u l d be r e c o v e r e d ,
not c ry s ta lliz e
a f t e r steam d i s t i l l i n g
but the aldehyde did
t h e d i o x a n e away fro m
t h e r e a c t i o n m i x t u r e . By a d d i n g a n e x c e s s o f d i l u t e
s o d iu m
h y d r o x i d e , a n o i l y p r o d u c t was o b t a i n e d w h i c h c o u l d be c r y s ­
tallized
by l a y e r i n g t h e
b asic m ix tu re w ith petroleum e t h e r .
I t was d i f f i c u l t t o p u r i f y t h i s compound s i n c e
its
t u r e c o e f f i c i e n t o f s o l u b i l i t y was s m a l l . On t h e
p r e v io u s work, how ever,
it
i s probable
basis of
t h a t t h i s compound
is 3 -m eth y l-6 ,7 -d im eth o x y iso q u in ald ald eh y d e
wor k i s
tem pera­
in p ro g ress in these la b o r a to r ie s
( IV .). F u rth er
on t h e p r e p a r a t i o n
and c o n d e n s a t i o n s o f t h i s a ld e h y d e .
CHO
1
c h 3- o - ^ / X v " " N
c h 3 " ° " \ vA
sY ” CH3
IV.
D e t a i l s o f th e O x id a t1o n s . - 1 - M e th v lis o a u in o lin e
oxidized
by d r o p p i n g a s o l u t i o n o f s e l e n i u m d i o x i d e i n d i ­
ox a n e i n t o a s o l u t i o n o f t h e
cip itate
is
of selenium form s,
reactio n th is p re c ip ita te
base
in dioxane. A red p re ­
but d u r in g th e c o u rse o f the
tu rn s
b l a c k . A f t e r rem oval of
the selenium and th e d io x a n e , th e i s o q u i n o l i n e aldehyde
-3 2
i s recovered
by s t e a m d i s t i l l a t i o n ,
steam d i s t i l l a t e
s e p a r a t i n g from t h e
i n b e a u t i f u l w hite n e e d l e s . T h is o x id a ­
t i o n i s n o t e a s y a n d c e r t a i n p r e c a u t i o n s m u s t be f o l l c w e d .
It
i s n e c e s s a r y to use v ig o ro u s m e c h a n ic a l s t i r r i n g
out the r e a c tio n ,
and th e
thro u g h ­
s o l u t i o n of s e le n iu m d i o x i d e must
be a d d e d t o t h e s o l u t i o n o f
1-m
eth y liso q u in o lin e
so t h a t
t h e r e w i l l n e v e r be a n e x c e s s o f s e l e n i u m d i o x i d e p r e s e n t
i n t h e r e a c t i o n m i x t u r e . An e x c e s s o f s e l e n i u m d i o x i d e w o u ld
cause f u r t h e r o x id a tio n to i s o q u in a ld ic a c i d .
T h is o x id a tio n did n o t proceed as r e a d i l y as the o x i­
datio n
and
o f l e p i d i n e and q u i n a l d i n e . A c c o r d i n g t o K w a r t l e r
L in d w a ll^
lep id in e
oxidation is
co m p lete f o r q u i n a l d i n e and
a f t e r two h o u r s . H e r e , h o w e v e r ,
datio n is
in su ffic ie n t,
isoquinoline
two h o u r s of o x i ­
an d a c o n s i d e r a b l e a m o u n t o f
increased to th ree hours,
i n c r e a s e d and
eth y l­
c a n be r e c o v e r e d a s a n o i l c o n t a m i n a t i n g t h e
a l d e h y d e a f t e r s t e a m d i s t i l l a t i o n . When t h e
tio n is
1-m
1 -m
eth y liso q u in o lin e
tim e o f o x i d a ­
th e y i e l d of aldehyde
is
i s no l o n g e r fo und c o n ­
ta m in a tin g the p r o d u c t.
The o x i d a t i o n o f l , 3 - d i m e t h y l - 6 , 7 - m e t h y l e n e d i o x y i s o q u i n o lin e
i s q u i t e s i m p l e . The a b o v e p r e c a u t i o n s a r e f o l l o w e d ,
an d t h e
o x id a tio n i s allow ed to p ro c e e d f o r th re e h o u r s .
Both t h e
i s o l a t i o n and t h e p u r i f i c a t i o n a r e e a s y .
m e r e ly n e c e s s a r y t o steam d i s t i l l
filte r
It
is
o f f t h e d i o x a n e an d t h e n
t h e c r u d e a ld e h y d e from t h e r e s i d u e l e f t
in the d i s ­
t i l l a t i o n f l a s k . A f t e r w a s h i n g w i t h s o d iu m h y d r o x i d e t o r e ­
I
-3 3 -'
move a n y a c i d ,
t h e a l d e h y d e c a n be c r y s t a l l i z e d e a s i l y f ro m
toluene or e th y l a lc o h o l.
The d i f f i c u l t i e s
in the o x id a tio n of 1 ,3 -d im e th y l-6 ,7 -
d im e th o x y iso q u in o lin e are d isc u sse d in the p reced in g s e c ­
tio n .
C o n d e n s a t i o n s o f I s o q u i n a l d a l d e h y d e K w a r t l e r an d
L i n d w a l l ^ ® h a v e shown t h a t q u i n o l i n e - 8 - a l d e h y d e a n d q u i n o ­
l i n e -4 -a ld e h y d e w i l l undergo c o n d e n s a tio n w ith a v a r i e t y of
" a c t i v e m e t h y l e n e " c o m p o u n d s . I t was n o t ,
th erefo re,
p r i s i n g t h a t i s o q u i n a l d a l d e h y d e was f o u n d t o
tiv e
sur­
be q u i t e a c ­
in condensation r e a c tio n s .
The c o n d e n s i n g a g e n t s u s e d i n t h i s s e c t i o n o f t h e r e ­
s e a r c h a r e a l l w e l l known. M ild o r g a n i c
araine w e r e f i r s t
bases such as d ie th y l-
u s e d by K n o e v e n a g e l 4® a n d h a v e f o u n d e x ­
t e n s i v e use s i n c e t h a t t i m e . Such a g e n t s a s sodium h y d r o x ­
i d e a n d s o d iu m e t h y l a t e a r e ,
need no f u r t h e r
o f c o u r s e , w e l l k n o w n , and
in tro d u ctio n .
In o rd e r t o t e s t
isoquinaldaldehyde
t o undergo c o n d e n s a tio n ,
for its a b ility
i t was c o n d e n s e d w i t h n i t r o m e t h a n e .
Such a c o n d e n s a tio n should g iv e a rough i d e a of th e e a se
w ith which t h i s a ld e h y d e w i l l co n d en se,
f o r nitrom ethane
h a s been u s e d i n c o n d e n s a t i o n s w i t h a number o f s i m i l a r
aldehydes, e .g .
q u i n o l i n e - 2 - a l d e h y d e and q u i n o l i n e - 4 - a l d e -
h y d e . When a f e w d r o p s o f d i e t h y l a m i n e w e r e a d d e d t o a l i t ­
tle
of th e aldehyde suspended in n itro m e th a n e , th e r e a c t i o n
m ixture
became w a r m . A f t e r c o o l i n g an d a d d i n g a l i t t l e
-3 4 -
w ater,
the c o n d e n s a tio n p ro d u ct could
tallize
be made t o c r y s ­
by v i g o r o u s s c r a t c h i n g .
T his co n d e n sa tio n product i s
quite
u n stab le;
composes on s t a n d i n g and g r a d u a l l y l o s e s i t s
i t de­
cry stallin e
f o rm * A t t e m p t s a t p u r i f i c a t i o n w e r e q u i t e u n s u c c e s s f u l
since
t h e l e a s t amount of warming i n d u c e d d e c o m p o s i t i o n .
A tte m p te d r e c r y s t a l l i z a t i o n from e t h y l a l c o h o l and w a te r
gav e a n o i l y m a t e r i a l w h i c h c o u l d n o t be i n d u c e d t o s o l i d i ­
f y . The com pound c r y s t a l l i z e d
point a f te r
from l i g r o i n ,
but th e m e ltin g
s u c h a r e c r y s t a l l i z a t i o n was b r o a d a n d l o w e r
t h a n th e m e l t i n g poir^t o f th e
o rig in al
sam ple,
t h a t d e a l d o l i z a t i o n had o c c u r r e d . I f th e
in d icatin g
sta rtin g
com ponents
w e r e p u r e , h o w e v e r , a r e a s o n a b l y p u r e s a m p l e c o u l d be r e ­
c o v e r e d . By c o n s i d e r a t i o n o f i t s m e t h o d o f p r e p a r a t i o n ,
its
in stab ility ,
was c o n c l u d e d t o
and a n a l y s i s f o r n i t r o g e n ,
t h e compound
be o f - n i t r o m e t h y l - l - i s o q u i n o l i n e m e t h a n o l
(V .).
V.
K w a r t l e r a n d L i n d w a l l 4 5 h a v e shown t h a t q u i n o l i n e - 2 a l d e h y d e 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 t o g i v e a " o n e t o one"
3€—
co n d e n sa tio n pro d u ct having th e s tr u c t u r e g iv e n fo r A .
W ith q u i n o l i n e - 4 - a l d e h y d e
t h e y o b t a i n e d a "two t o
p r o d u c t t o w h i c h was a s s i g n e d t h e
one"
s t r u c t u r e a s shown
for B
/ N
/ n\
B
D uring p r e l i m i n a r y c o n d e n s a tio n s of is o q u in a ld a ld e h y d e
w ith acetophenone in th e p resen ce
o f s o d iu m h y d r o x i d e i t
ap­
p e a r e d t h a t a m i x t u r e o f p r o d u c t s was b e i n g o b t a i n e d . T h i s
c o n d e n s a t i o n was t h e r e f o r e
s tu d ie d w ith the id e a of f in d in g
w hat t h e p r o d u c t s were and u n d er what c o n d i t i o n s e a c h c o u ld
be o b t a i n e d . I t was h o p e d t h a t p e r h a p s a l l
sib le
c o n d n e s a tio n p r o d u c ts could
three
o f the p o s ­
be i s o l a t e d t h u s b e a r i n g
-3 6 -
o u t th e c o u r s e o f a c o n d e n s a t i o n i n which a "two t o one"
product i s produced.
The c o u r s e o f a n o r d i n a r y " o n e t o o n e " c o n d e n s a t i o n i s
gen erally
b eliev ed to take p lace
by p r e l i m i n a r y f o r m a t i o n
o f an a l d o l p r o d u c t , w hich h a s been i s o l a t e d
i n many c a s e s ,
f o l l o w e d by l o s s o f w a t e r t o g i v e a n u n s a t u r a t e d c o m p o u n d .
M ichael has p o s t u l a t e d t h a t i f an u n s a tu r a te d
bond i s a d ­
ja c e n t to a carbonyl or carbethoxy group, f u r th e r conden-
.
s a t i o n can tak e p la c e w ith th e a d d i t i o n of th e addenda
a c r o s s t h e d o u b l e bond i n s u c h a f a s h i o n t h a t t h e new c a r ­
bon g o e s t o t h e c a r b o n f u r t h e s t r e m o v e d f r o m t h e c a r b o n y l
gro u p and th e h y d ro g e n goes t o th e
carbon a d j a c e n t t o the
c a r b o n y l . Th us a n u m b e r o f w o r k e r s ^ 9 h a v e shown t h a t
presence
i n the
o f a s m a ll amount o f a l k a l i fl(-p h en y lacry lo p h en o n e
w i l l add a m olecule
o f d i e t h y l m a l o n a t e a s shown b e l o w :
0
Q H -C H 2 -C — ^
CH2 - C 0 0 C 2 H5
COOCoHc
I t was f o u n d t h a t
i f an excess of isoquin ald ald eh y d e
was c o n d e n s e d w i t h a c e t o p h e n o n e i n a c o l d w a t e r - a l c o h o l m i x ­
ture
i n th e p r e s e n c e o f a q u e o u s sodium h y d r o x i d e ,
t h a t tw o
d i f f r e n t p r o d u c t s r e s u l t e d . I f t h e r e a c t i o n m i x t u r e w as f i l ­
tered a fte r
15 o r 20 m i n u t e s o f r e a c t i o n , a c o n d e n s a t i o n
p roduct corresponding in g e n e ra l p r o p e r t i e s to those expected
■
-3 7 -
f o r a n a l d o l compound w as o b t a i n e d . T h i s p r o d u c t was u n s t a b l e
a n d c o u l d n o t be c r y s t a l l i z e d r e a d i l y w i t h o u t d e c o m p o s i t i o n .
I t s n i t r o g e n a n a l y s is corresponded to t h a t expected f o r
^-h ydroxy-^rl-isoquinolylpropiophenone
n o t the
( V I . ) , a n d i t w as
u n s a t u r a t e d compound f o r m e d by t h e l o s s o f w a t e r ,
f o r t h i s was p r e p a r e d i n s u b s e q u e n t w o r k .
0
H ,OH
II
V —CHo-C-<
V I.
I f t h e c o n d e n s a t i o n w i t h a c e t o p h e n o n e was a l l o w e d t o
p r o c e e d f o r tw o o r t h r e e h o u r s , n o a l d o l compound was r e ­
c o v e r e d . I n s t e a d o f a n a l d o l p r o d u c t an u n s a t u r a t e d compound,
p r e s u m a b l y f o r m e d by t h e
l o s s o f w a t e r fro m t h e a l d o l ,
f o r m e d . T h i s compound was shown t o
w«s
be d i f f e r e n t f r o m ( V I . )
by a m i x e d 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 . Not o n l y was t h e
mixed m e l t i n g p o i g t d e p r e s s e d ,
but m icroscopic exam ination
r e v e a l e d t h a t t h e tw o c o m poun ds d i d n o t h a v e t h e same c r y s t a l
s t r u c t u r e . Compound V I . c r y s t a l l i z e d
lelepiped s,
as nearly p erfect p a ra l­
b u t t h e new p r o d u c t c r y s t a l l i z e d
in n e e d le s ,
w hich a p p e a r e d u n d er t h e m ic ro s c o p e a s e lo n g a t e d h e x a g o n a l
p r i s m s . On t h e
b a s is o f a n a ly s e s f o r carbon, hydrogen,
n i t r o g e n i t was c o n c l u d e d t h a t t h i s
an d
compound w a s ^ - l - i s o q u i n o -
38-
lylacry lo p h en o n e
(V II.)
0
If
C H ^ CHC
>
- <
/V S l
w
V II.
Compound V I I . . was s y n t h e s i z e d
under d i f f r e n t
co n d itio n s,
by c o n d e n s a t i o n o f a n e x c e s s o f i s o q u i n a l d a l d e h y d e w i t h
acetophenone i n th e p re se n c e
cedure
o f s o d iu m e t h y l a t e . T h i s p r o ­
i s much s i m p l e r t h a n t h e one o u t l i n e d a b o v e . I t
is
m e r e l y n e c e s s a r y t o t r e a t a s o l u t i o n o f t h e two r e a c t a n t s
i n a b s o l u t e a l c o h o l w i t h one o r two d r o p s o f sodium e t h y l a t e
so lu tio n ,
the m ix tu re
V II. c ry s ta lliz e s
b e c o m e s q u i t e warm a n d a f t e r
i n n e e d l e s a n d may be f i l t e r e d
standing,
o f f . M icro­
s c o p i c e x a m i n a t i o n , m ixed 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 and
a n a l y s e s f o r c a rb o n , h y d r o g e n , and n i t r o g e n r e v e a l e d no d i f frence
in the sam ples o b ta in e d
by t h e two m e t h o d s #
By c o n d e n s i n g a c e t o p h e n o n e w i t h l e s s t h a n a n e q u i - m o l e c u l a r amount of i s o q u i n a l d a l d e h y d e
hydroxide, a c r y s t a l l i n e
i n t h e p r e s e n c e o f sodium
p r o d u c t w as o b t a i n e d a f t e r 18 t o
24 h o u r s w h i c h d i d n o t r e s e m b l e t h e
u n s a t u r a t e d " o n e t o one"
condensation p ro d u c t. A fte r p u r i f i c a t i o n
fr o m e t h y l a l c o h o l , t h i s
g u la r w hite p l a t e s
by r e c r y s t a l l i z a t i o n
compound a p p e a r e d a s s m a l l r e c t a n ­
stria te d
along the s h o rt a x i s . A product
-3 9 -
of id e n tic a l c r y s ta llin e
y ield s
f o r m c o u l d be o b t a i n e d i n
b etter
by c o n d e n s a t i o n o f a n e x t f e s s o f a c e t o p h e n o n e w i t h i s o ­
q u i n a l d a l d e h y d e i n t h e p r e s e n c e of a l i t t l e
s o d iu m e t h y l a t e .
A m i x e d 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 t h e s e tw o s a m p l e s g av e
n o d e p r e s s i o n . S u b s e q u e n t e x a m i n a t i o n an d a n a l y s e s showed
these
two s a m p l e s t o
be i d e n t i c a l . On t h e
b asis of carbon,
h y d ro g e n , and n i t r o g e n a n a l y s e s a s w e ll a s a m o l e c u l a r w e ig h t
determ in atio n ,
i t w as c o n c l u d e d t h a t t h i s
s u b s t a n c e was
3 -(l-iso q u in o ly l)-l,5 -d ip h e n y l-l,5 -p e n ta n e d io n e
(V III.).
CH
>V III.
On t h e
b a s i s o f t h e p r o d u c t s i s o l a t e d f r o m t h e s o d iu m
h ydroxide c o n d e n s a tio n s o f iso q u in a ld a ld e h y d e w ith a c e to p h e ­
none,
i t was e v i d e n t t h a t t h e f o r m a t i o n o f a " t w o t o
p r o d u c t had t a k e n p l a c e
one"
by a s e r i e s o f r e a c t i o n s i n v o l v i n g
i n i t i a l f o r m a t i o n o f a n a l d o l p r o d u c t . The a l d o l compound
(V I.) f i r s t
form ed and t h e n i n t h e p r e s e n c e o f sodium hy­
d roxide s p l i t
(V II.)
o f f w a te r to give the
u n s a t u r a t e d compound
which t h e n added a n o t h e r m o lecule o f a c e to p h e n o n e t o
-4 0 -
give th e
"two t o
one" p r o d u c t
(V III.).
C ondensations of iso q u in ald ald eh y d e w ith d e r iv a tiv e s
o f p h e n y l a c e t i c a c i d a r e f a r more i n t e r e s t i n g
point of attem p tin g to
n a tu re to the
sy n th esize
from t h e v ie w ­
s tr u c tu r e s s im ila r in
iso q u in o lin e a lk a lo id s .
A t t e m p t s w e r e f i r s t made t o c o n d e n s e i s o q u i n a l d a l d e h y d e
(II.)
w i t h s o d iu m p h e n y l a c e t a t e ,by a P e r k i n t y p e o f c o n d e n ­
s a t i o n . The c o n d i t i o n s , h o w e v e r , w e r e f a r t o o d r a s t i c ;
r e a c tio n m ixture
becam e d a r k and no c r y s t a l l i n e
the
product
c o u l d be o b t a i n e d . E v e n when t h i s c o n d e n s a t i o n was a t t e m p t e d
a t room t e m p e r a t u r e , e x t e n s i v e d e c o m p o s i t i o n o c c u r r e d . Con­
d e n s a t i o n s o f th e P e r k i n ty p e were a b a n d o n e d ,
type o f s t r u c t u r e
w as o b t a i n e d
but th e d e s ir e d
by e m p l o y i n g d e r i v a t i v e s o f
phenylacetic a c id .
W ith p h e n y l a c e t o n i t r i l e , c o n d e n s a t i o n c o u ld
q u i t e e a s i l y . Two m e t h o d s w e r e u t i l i z e d
In the p resen ce
which c o u ld
for th is
be o b t a i n e d
condensation
o f d i e t h y l a m i n e a n o i l y p r o d u c t was o b t a i n e d
be b r o u g h t i n t o a c r y s t a l l i n e
c o n d i t i o n by e x ­
t r a c t i o n w i t h b a s e a n d r e c r y s t a l l i z a t i o n f r o m a n a l c o h o l an d
w a t e r m i x t u r e . T h i s p r o d u c t p r o v e d t o be i d e n t i c a l w i t h a
condensation p ro d u ct o btained
by t r e a t i n g e q u i v a l e n t a m o u n t s
of is o q u in a ld a ld e h y d e and p h enyl a c e t o n i t r i l e
w ith a l i t t l e
s o d iu m e t h y l a t e d i s s o l v e d i n a b s o l u t e e t h y l a l c o h o l . The l a t ­
t e r c o n d e n s a t i o n was more s a t i s f a c t o r y , a s i t w as q u i t e
an d g a v e much b e t t e r y i e l d s ,
N itrogen,
carbon,
sim pl
i n t h e n e i g h b o r h o o d o f 90 %•
and hydrogen a n a ly s e s t o g e t h e r w ith th e
-4 1 -
e x p e r i m e n t a l y i e l d showed t h i s compound t o be a " o n e t o One"
u n s a t u r a t e d c o n d e n s a t i o n p r o d u c t w h i c h w as c o n c l u d e d t o be
o (-p h en y l-i-iso q u in o lin ea cry lo n itrile
(IX .) .
CN
IX.
T a b le of E x p e r i m e n t a l and Q a l c u l a t e d D a t a f o r IX.
C alculated
A ldol
Carbon
V alues.
U nsaturated
V alues fo u n d .
"Two t o one"
78.82
84.36
83.60.
84.44
N itro g e n 10.29
10.93
11.26
10.94
4.72
5.13
4.83
Hydrogen 6 .63
Y ield
0.82
0.57
0.7 5
( B a s e d on 0 . 5 g o f a l d e h y d e a n d 0 . 4 g o f n i t r i l e ) .
C ondensation w ith e th y l p h e n y la c e ta te
should give r i s e
t o a p r o d u c t w i t h t h e same c a r b o n s k e l e t o n a s was o b t a i n e d
by c o n d e n s a t i o n w i t h p h e n y l a c e t o n i t r i l e . H o w e v e r , t h e com­
p o u n d o b t a i n e d by c o n d e n s a t i o n o f i s o q u i n a l d a l d e h y d e
(II.)
a n d e t h y l p h e n y l a c e t a t e was n o t u n s a t u r a t e d . I t c r y s t a l l i z e d
i n b e a u t i f u l w h i t e n e e d l e s fro m e t h y l a l c o h o l , a n d a n a l y s i s
o f a sample p u r i f i e d i n t h i s manner c o r r e s p o n d e d t o t h a t
w h i c h w o u l d be e x p e c t e d f o r t h e e t h y l e s t e r o f
iso q u in o lin ep ro p io n ic acid
(X .).
-pheny^-l-
42*
It
s h o u l d be p o i n t e d o u t t h a t a l t h o u g h n i t r o g e n a n a l y s e s
alone a re
in c o n c lu s iv e in d e te rm in a tio n of the s tr u c t u r e
of
t h e c o n d e n s a t i o n p r o d u c t of i s o q u i n a l d a l d e h y d e and e t h y l
phen ylacetate,
th e carb o n v a lu e s d i f f e r f o r the
three pos­
sib le
by s e v e r a l p e r c e n t . The r e s u l t s
of the a n a l­
products
y s i s a r e compared w ith th e t h e o r e t i c a l v a l u e s i n th e t a b l e
g iv e n below .
COOC2 H5
|
C
v
CH-
v
X.
T a b l e o f E x p e r i m e n t a l a n d C a l c u l a t e d V a l u e s f o r X.
C alculated
A ldol
V alues.
U nsaturated
V alues fo u n d .
11Two
to
o n e 11
7 4.72
79.47
77.06
74.46
N itrogen
4.36
4.62
3 .0 0
4.47
Hydrogen
5.98
5.40
6 .25
5.61
Carbon
The p r o d u c t s o b t a i n e d
of c o n s i d e r a b l e
by t h e l a s t two c o n d e n s a t i o n s a r e
i n t e r e s t . I f t h e i r s t r u c t u r e s a r e compared
w ith th e s t r u c t u r e s o f the is o q u in o lin e a l k a l o i d s
In tro d u ctio n to th is th e s is ),
( see the
i t c a n be s e e n t h a t t h e y d i f f e r
-4 3 -
from t h e a l k a l o i d s i n t h e i r b a s i c
c a r b o n s k e l e t o n by t h e
i n t r o d u c t i o n o f a s e c o n d c a r b o n a to m b e t w e e n t h e p h e n y l and
i s o q u i n o l y l n u c l e i . Such compounds, p a r t i c u l a r l y
be o f i n t e r e s t
(X .) should
because of p o s s ib le p h y s io lo g ic a l a c t i v i t y .
C o n d e n s a tio n o f i s o q u i n a l d a l d e h y d e s w i t h " a c t i v e m ethylene"
co m p o u n d s c o n s t i t u t e s a new m e t h o d o f s y n t h e s i s o f i s o q u i n o ­
l i n e s . The p o s s i b l e v a l u e o f s u c h a m e t h o d o f s y n t h e s i s w i l l
be d i s c u s s e d i n g r e a t e r d e t a i l i n t h e
fo llo w in g s e c tio n .
S u g g e s t e d E x t e n s i o n s o f t h i s - Re s e a r c h . - A new m e t h o d o f
s y n t h e s i s o f i s o q u i n o l i n e s has been s u g g e s te d i n t h i s r e ­
search,
a n d c e r t a i n p h a s e s o f t h e w o r k m i g h t be e x t e n d e d w i t h
p r o m is in g r e s u l t s . A few o f th e p o s s i b l e e x t e n s i o n s have
been i n d i c a t e d
b r i e f l y below:
1. Since a n i t r i l e
d esitab le
lin e,
it
group and an u n s a t u r a t e d l i n k a re n o t
i f n arco tic p ro p e rtie s are d esired
in an isoquino­
v /o uld be i n t e r e s t i n g t o p r o c e e d f u r t h e r w i t h t h e
c o n d e n s a tio n p ro d u c t of iso q u in a ld a ld e h y d e and phenyl a c e to ­
n itrile
(IX .).
T h i s compound c o u l d p r e s u m a b l y be e s t e r i f i e d
w ith e t h y l a lc o h o l in the presence
of hydrogen c h l o r id e ,
and
t h e r e s u l t i n g e s t e r m i g h t be r e d u c e d t o r e m o v e t h e d o u b l e
bond, p r o d u c i n g e i t h e r t h e e t h y l e s t e r o f « f - p h e n y l - ^ - ( l , 2 , 3 , 4 t e t r a h y d r o i s o q u i n o l i n e - l ) - p r o p i o n i c a c i d o r t h e efcJtyl e s t e r
of o (-p h e n y l-l-iso q u in o lin ep ro p io n ic a c id .
2 . There a r e a l a r g e number o f exam ples o f r e d u c t i o n of
i s o q u i n o l i n e s to t e t r a h y d r o i s o q u i n o l i n e s , and in g e n e r a l,
t e t r a h y d r o i s o q u i n o l i n e s a r e more p o t e n t p h y s i o l o g i c a l l y
-4 4 -
th a n the
unreduced is o q u in o lin e s .
It
should, t h e r e f o r e ,
prove o f i n t e r e s t t o red u ce the i s o q u i n o l y l n u c le u s i n
c o n d e n s a t i o n p r o d u c t s such a s the p r o d u c t o b t a i n e d from
th e c o n d e n s a tio n of iso q u in a ld a ld e h y d e and e t h y l p h e n y lacetate
and th e p r o d u c t o b t a i n e d i n ( 1 ) a b o v e .
3 . There a re
a l a r g e nu m b er
a c e t i c a c i d s which sh o u ld prove
d en satio n s,
of s u b s t i t u t e d p h e n y lof i n t e r e s t i n t h e i r con­
e s p e c ia lly those s u b s titu te d
i n th e Z and A
p o s i t i o n s w ith m ethoxyl g ro u p s, f o r the n a t u r a l l y o c c u r r i n g
is o q u in o lin e s g e n e r a lly c a rry groups in th e se p o s i t i o n s .
i
W i t h co m p o u n d s c o n t a i n i n g a h y d r o x y l g r o u p i n t h e o r t h o
p o sitio n ,
acid ,
it
bridge
such a s th e e th y l e s t e r of jj-h y d ro x y p h e n y la c e tic
should prove p o s s ib le to c o n s t r u c t a l a c t o n e - l i k e
by h e a t i n g t h e c o n d e n s a t i o n p r o d u c t w i t h d i l u t e
m in era l a c i d s . Such la c to n e
b ridges occur in s e v e r a l
the
but
isoquinoline
th a t is
w ith the
alk alo id s,
i n the r e v e r s e
of
order,
c a rb o x y l a tta c h e d to the p h en y l n u c l e u s .
4. C ondensations of 3 -m e th y l-6 ,7 -m eth y len ed io x y iso q u in aldaldehyde
s h o u l d be s t u d i e d ,
and t h e o x i d a t i o n o f 1 , 3 -
d im e th y l-6 ,7 -d im e th o x y is o q u in o lin e to g e th e r w ith the
d en satio n products
con­
o f th e a ld e h y d e formed s h o u ld a l s o
i n v e s t i g a t e d . S u c h c o n d e n s a t i o n s w ould g i v e r i s e
be
to i s o ­
q u i n o l i n e d e r i v a t i v e s c o n t a i n i n g most o f t h e g r o u p s p r e ­
sent in p h y sio lo g ic a lly active a lk a lo id s.
5 . O t h e r i s o q u i n a l d a l d e h y d e s m i g h t be p r e p a r e d . I t
should prove p o s s i b l e t o s y n th e s iz e
both 6 , 7 - m e t h y l e n e -
45-
d i o x y i s o q u i n a l d a l d e h y d e , and
6
, 7 -d im e th o x y i3 oquinaldaldehyde
A suggested s y n th e s is f o r the 6 ,7 -m e th y le n e d io x y iso q u in a ld aldehyde i s o u t l i n e d
below and i s
b a s e d on r e a c t i o n s d i s ­
cu ssed p r e v io u s ly i n t h i s t h e s i s . A s i m i l a r s e r i e s of r e a c ­
t i o n s should g iv e r i s e
to 6,7-dim ethoxyisoquinaldaldehyde.
«3
.0- ,
CHaCHC
HC1
ch2
0
0
NHg
-
NH
-
CHg
X>-
;h2
CHg
R a n e y Nicfc&l
HO
N
ch2
X 0-
Such a l d e h y d e s
cause of th e c l o s e
s h o u l d be o f c o n s i d e r a b l e
sim ila rity
in tere st
b e­
of p o s s ib le condensation p roducts
t o n a t u r a l l y o c c u r r i n g a l k a l o i d s s u c h a s p a p a v e r i n e and
h y d rastin e.
The s u b s t i t u t e d p h e n y l e t h y l a m i n e s s h o u l d be a v a i l a b l e ,
a n d one s u g g e s t e d s y n t h e s i s i s o u t l i n e d
o -^ V
CHp
\ 80
CHO
below:
CHO
or
H
CH3-0-
ArCHO
46
Ar CHO+ CH3 -NO2
NaOEfr_
ArCH 0 H-CH 2 -NC>2
S n C l2
1
(See Appendix)
HC1
Hg
Ar-CH2 -CH2-NH2
Ni
A r - C H 2 -C H = N 0 H
■
-4 7 -
CHAPTER I I I .
EXPERIMENTAL
PART.
l*Me t h y l - 3 . 4 - d i h y d r o i soq u i n o l i n e .
ch3
/
n
/ V
*
Hi
1
To 20 g . o f N - a c e t y l p h e n y l e t h y l a m i n e d i s s o l v e d
120
cc.
o f t e t r a l i n was a d d e d
20
g . of phosphorus p en to x -
i d e s u s p e n d e d i n 50 c c . o f t e t r a l i n .
f l u x e d f o r 10 m i n u t e s . F i f t e e n g .
in
The m i x t u r e was r e ­
of phosphorus p en to x id e
i n 50 c c . o f t e t r a l i n w as a d d e d a n d r e f l u x i n g c o n t i n u e d
f o r 10 m i n u t e s . A t h i r d p o r t i o n o f 10 g . o f p h o s p h o r u s
p e n t o x i d e was a d d e d a n d t h e r e f l u x i n g c o n t i n u e d f o r a n
ad d itio n al
10
m inutes.
D uring th e co u rse
of the r e f l u x i n g a black t a r
sepa­
r a t e d f r o m t h e m i x t u r e . S t i r r i n g was a t t e m p t e d t h r o u g h ­
out the r e a c t i o n ,
but the t a r g e n e r a l l y i n t e r f e r e d w ith
efficien t stirrin g .
The m i x t u r e was a l l o w e d t o c o o l an d t h e
bulk o f th e
t e t r a l i n p o u r e d o f f . The t e t r a l i n was b o i l e d w i t h 250 c c .
o f w a t e r . A f t e r c o o l i n g , t h e w a t e r l a y e r was p o u r e d o v e r
t h e r e a c t i o n t a r and a f t e r
sid ed ,
th e v ig o ro u s r e a c t i o n had sub­
b r o u g h t t o b o i l i n g an d b o i l e d f o r s e v e r a l m i n u t e s .
-4 8
A f te r s e p a r a tio n of excess t e t r a l i n ,
the aqeous la y e r
w as made s t r o n g l y b a s i c w i t h s o d i u m h y d r o x i d e
1-m eth y l- 3 , 4 -d ih y d ro iso q u in o lin e
( 1 0 % ) . The
s e p a r a t e d a s a n o i l and
w as t a k e n up i n b e n z e n e . The b e n z e n e l a y e r was s e p a r a t e d ,
and th e
b e n z e n e was r e m o v e d by vacuum d i s t i l l a t i o n
s t e a m b a t h . The p r o d u c t was t h e n vacuum d i s t i l l e d
on a
and th e
f r a c t i o n c o m i n g o v e r f r o m 1 0 0 ° t o 1 4 0 ° a t 12 mm. was r e ­
t a i n e d . T h i s w as r e d i s t i l l e d ,
q u inoline d i s t i l l e d
a t 12 mm. t h e d i h y d r o i s o -
b e t w e e n 1 2 7 ° an d 1 3 3 ° .
The y i e l d w as 7 . 1 g r a m s o r 40 % o f t h e t h e o r y .
The compound was i d e n t i f i e d by i t s
p i c r a t e ; M .P . 193-1940 *
49
TABLE OF YIELDS OF 1 -METHYL-3, 4-DIHYDROISOQUINOLINE.
S olvent
Agent
Tem perature
Time
S tartin g
Y ield
in hours m a te ria l
i n grams*
T e tralin
P0C1 3
100- 120
°
fin ish at
1800
3-4
T etralin
POCI 3
140°
Xylene
POCI 3
140°
C hloroform PO C l3
61°
48
20
20
26 %
i
38
26 %
6
20
4 %
%
X ylene
p2°5
140°
I2
40
21
%
Xylene
P2°5
140°
I2
8
22
%
2°5
206°
1
2
20
40 %
B oiling
4
10
27 %
T e tralin
L ig ro in
p
POCI 3
A IC I3
-5 0
1-MethylisoQUinoline (1.).
CH3
N
To 1 5 g . o f l - m e t h y l - 3 , 4 - d i h y d r o i s o q u i n o l i n e p l a c e d
i n a sm all C la is e n d i s t i l l a t i o n
fu ll
f l a s k was a d d e d a s p a t u l a
o f R a n e y N i c k e l . The m i x t u r e was h e a t e d . A v i g o r o u s
b u b b l i n g s o o n com m enced, h y d r o g e n w as e v o l v e d an d c o u l d
be i g n i t e d a t t h e m o u t h o f t h e f l a s k . The b u b b l i n g c o n ­
tinued fo r
risin g
1 0 -2 0
m in u te s , th e te m p e r a tu re of the m ix tu re
slow ly d u rin g t h i s
t i m e . H e a t i n g was c o n t i n u e d
u n t i l the tem perature reached 248°,
1
th» b o ilin g p o in t o f
- m e t h y l i s o q u i n o l i n e . ' The p r o d u c t was t h e n vacuum d i s t i l l e d .
Y i e l d 7 0 - 7 5 % . B . P . 1 2 4 - 1 2 6 ° a t 10 mm.
The b o i l i n g p o i n t o f t h e 1 - m e t h y l i s o q u i n o l i n e t h u s o b ­
t a i n e d w as 2 4 8 ° , t h a t l i s t e d
(lo c .
sit.)
i n the l i t e r a t u r e
by P o m e r a n z
w a 3 2 4 8 ° . The d e n s i t y w as d e t e r m i n e d a t 2 6 °
w i t h r e f e r e n c e t o w a te r a t 4° and found t o
d e n s i t y f o u n d by J a n t z e n ( l o c .
sit.)
be 1 . 0 6 4 . The
was 1 . 0 7 7 7 a t 2 0 ° ;
a c c o r d i n g t o B r i i h l 5®, 1 . 0 7 6 3 a t 2 0 . 5 ° .
51-
D e r l v a t l v e s of l - M e t h y l i s o q u i n o l i n e .
P l c r a t e . P r e p a r e d a c c o r d i n g t o t h e method o f S p a t h and
co-w orkers ( lo c . s i t . ) .
M .P.
R ec ry stallized
from e t h y l a l c o h o l .
230-232-° ( w i t h d e c o m p o s i t i o n ) .
A nal.
C a l c d . f o r C 1 6 H1 2 N4 O7 : N, 1 5 . 0 6 .
Found: N 1 5 .0 1 , 1 5 .0 0 .
D ic h r o m a te . P r e p a r e d a c c o r d i n g t o th e m ethod o f P i c t e t
a n d Gams ( l o c . s i t . ) .
D e c o m p o s i t i o n b e t w e e n 1 5 5 ° a n d 160 °*
S u l f a t e . P r e p a r e d by a d d i n g a c a l c u l a t e d a m o u n t o f d i l u t e
s u lf u r ic acid to
dryness. P u rified
1
- m e t h y l i s o q u i n o l i n e and e v a p o r a t i n g t o
by p r e c i p i t a t i o n f r o m e t h y l a l c o h o l w i t h
e t h e r . The s u l f a t e w as d r i e d o v e r
Prepared p rev io u sly
M .P. 2 4 6 - 2 4 8 ° .
by P o m e r a n z ( l o c . s i t . ) .
H y d r o c h l o r i d e . The h y d r o c h l o r i d e was p r e p a r e d i n a m a n n e r
analagous to t h a t used f o r the
s u l f a t e . M .P. 2 0 0 - 2 0 5 ° . p r e ­
p a r e d p r e v i o u s l y by P i c t e t an d Gams who r e p o r t e d a m e l t i n g
p o in t of about 170°.
C h l o r o p l a t i n a t e . The c h l o r o p l a t i n a t e
of 1-m eth y liso q u in o ­
l i n e was p r e p a r e d
so lu tio n of chloro-
by a d d i n g a d i l u t e
p l a t i n i c acid to a s o lu t i o n of
1
-m eth y liso q u in o lin e
in
d i l u t e h y d r o c h l o r i c a c i d . The c h l o r o p l a t i n a t e w a s f i l t e r e d
o f f and r e c r y s t a l l i z £ d
f r o m a l c o h o l a n d w a t e r . The o r a n g e
52-
c r y s t a l s t h u s o b t a i n e d w er e d r i e d f o r s e v e r a l d a y s i n a
vacuum d e s s i c a t o r o v e r s u l f u r i c a c i d . M . P . 2 3 3 - 2 3 4 ° .
A number o f w o rk e rs have r e p o r t e d c h l o r o p l a t i n a t e s
1
of
-m e th y lis o q u in o lin e w ith a v a r i e t y of m eltin g p o i n t s ,
th ese are l i s t e d
i n the d i s c u s s io n .
A n a l . By m e t a l l i c r e s i d u e .
C a l c d . f o r GgQHgQNgClgPt • P t 2 8 . 0 0 .
Found: 2 8 .1 6 .
M e t h i o d i d e . P r e p a r e d a c c o r d i n g t o t h e method o f M i l l s and
w orkers ( l o c .
s i t . ) . M .P. 2 0 8 ° .
53-
IsoquinaldaldehydeC lI. ) .
CHO
To a s o l u t i o n o f 10 g . o f 1 - m e t h y l i s o q u i n o l i n e
in
17 c c . o f d i o x a n e was a d d e d d r o p by d r o p , w i t h v i g o r o u s
m echanical s t i r r i n g ,
dioxide
i n 90 c c .
a s o l u t i o n of 8 .9 g .
of selenium
of dioxane w hich c o n ta in e d 3 c c .
of
w a t e r . The s e l e n i u m d i o x i d e s o l u t i o n was a d d e d d u r i n g
th e course
o f one h a l f a n h o u r w i t h g e n t l e w a r m i n g o f
t h e r e a c t i o n m i x t u r e . The r e a c t i o n m i x t u r e w as t h e n
h e a te d f o r t h r e e h o u rs under r e f l u x
on a b o i l i n g w a t e r
b a t h ( m e c h a n i c a l s t i r r i n g was c o n t i n u e d d u r i n g t h i s
r e f l u x i n g ) . D uring the a d d i t i o n of selenium d io x id e ,
s e le n iu m s e p a r a t e d a s a re d p r e c i p i t a t e w hich t u r n e d
black as the h e a tin g co n tin u ed . A f te r th re e hours of
reflux ing ,
the
s o l u t i o n was c o o l e d a n d t h e
filtered
o f f . The
bulk of the d io x a n e
o f f on a
w a t e r b a t h u n d e r v acu u m , a n d
d i s t i l l e d . D uring the f i r s t p a r t
selenium
w as d i s t i l l e d
th e r e s i d u e steam
of the d i s t i l l a t i o n
the r e s t
o f th e dioxane d i s t i l l e d
o f f a n d w as d i s c a r d e d .
When t h e
steam d i s t i l l a t e a p p e a r e d m i l k y , c o l l e c t i o n
54-
w as b e g u n . A b o u t 1 l i t e r
of d i s t i l l a t e
was c o l l e c t e d ;
a t th e end of t h i s f r a c t i o n th e d i s t i l l a t e no lo n g e r
became m i l k y o n c o o l i n g . The s t e a m d i s t i l l a t e
to s ta n d in the r e f r i g e r a t o r a t
0
w as a l l o w e d
° f o r tw elve t o tw e n ty -
four hours.
The i s o q u i n a l d a l d e h y d e c r y s t a l l i z e d
d istillate
in long,
th e m other l i q o u r ,
fro m t h e s t e a m
s i l k y , w h i t e n e e d l e s . By e x t r a c t i n g
after
aldehyde, w ith e t h e r ,
filterin g
o f f the is o q u in a ld ­
an d t h e n e v a p o r a t i n g o f f t h e e t h e r ,
a n a d d i t i o n a l a m o u n t o f a l d e h y d e was o b t a i n e d a s a n o i l .
T his
o i l could
ding
a
the
be b r o u g h t i n t o a c r y s t a l l i n e s t a t e
l i t t l e w a t e r and a l l o w i n g t h e m i x t u r e
by
ad­
to stan d in
refrig era to r.
The y i e l d a m o u n t e d t o 4 . 6 0 g r a m s o r 42 % o f t h e
th eo ­
re tic al .
M .P. 5 5 - 5 5 . 5 ° .
A nal.
C a l c d . f o r C 1 0 H7 N0: N , 8 . 9 2 ; C, 7 6 . 2 9 ; H , 4 . 4 9 .
F o u n d : N, 8 . 9 0 , 8 . 7 1 ,
P recautions to
8 . 9 2 ; C, 7 6 . 4 0 ; H 4 . 4 9 .
be f o l l o w e d . - I t h a s b e e n f o u n d t h a t
v ig o ro u s m echanical s t i r r i n g
r e a c t i o n . I t has a ls o
been found t h a t th e selenium d i o x i d e
s o l u t i o n m u s t be a d d e d t o
tim e h a s been v a r i e d ,
i s e s s e n t i a l throughout th e
t h e s o l u t i o n o f t h e a l d e h y d e . The
b u t i t was f o u n d t h a t i f t h e o x i d a t i o n
was s t o p p e d b e f o r e t h r e e h o u r s h a d e l a p s e d o x i d a t i o n w a s
in co m p lete.
P roperties
of I s o q u in a ld a ld e h y d e .-There
no tendency f o r h y d ra te fo rm a tio n a s th e re
s ee m s t o be
i s in th e case
o f t h e c o r r e s p o n d i n g q u i n o l i n e a l d e h y d e s . The a l d e h y d e
v e ry r e a c t i v e and re d u c e s T o l l e n 's r e a g e n t i n the
A s o d iu m b i s u l f i t e
is
co ld .
compound i £ f o r m e d s l o w l y . The a l d e h y d e
i s a s k i n i r r i t a n t an d i f
in h a le d , even in sm all q u a n t i t i e s ,
causes sneezing.
The a l d e h y d e
lig ro in ,
is
solu ble
and b e n z e n e . I t
d iffic u ltly
cry stallized
so lu b le
is
in a lc o h o l, acetone, e th e r ,
in so lu b le
i n c o l d w a t e r and
i n h o t w a t e r . The a l d e h y d e may be r e ­
from l i g r o i n . A sam ple r e c r y s t a l l i z e d
l i g r o i n an d d r i e d i n a vacuum d e s s i c a t o r
fro m
over s u l f u r i c
a c i d deaomposes slo w ly p r o d u c in g a re d p r o d u c t .
The i s o q u i n a l d a l d e h y d e may be o x i d i z e d w i t h h y d r o g e n
p e r o x i d e t o i s o q u i n a l d i c a c i d w h i c h may be r e c o v e r e d
fo rm a tio n of an in s o lu b le
copper s a l t
by
s a l t w i t h c o p p e r s a l t s . The g r a y i s h
c a n be d e c o m p o s e d w i t h h y d r o g e n s u l f i d e .
The a l d e h y d e c r y s t a l l i z e s f r o m w a t e r i n l o n g s l e n d e r
n e e d l e s . These n e e d l e s a r e w h ite and have a s i l k y a p p e a r a n c e .
56-
Sem icarbazone of I s o q u i n a ld a ld e h y d e »
0
f/
ch= n-nh-c-nh2
To 0 . 5 g . o f i s o q u i n a l d a l d e h y d e d i s s o l v e d i n a n a l c o ­
h o l a n d w a t e r m i x t u r e was a d d e d 0 . 3 5 g . o f s e m i c a r b a z i d e
hydrochloride d issolved
in a l i t t l e
w a t e r . The s o l u t i o n
w as warmed f o r t h r e e m i n u t e s on a s t e a m b a t h . A s l i g h t e x ­
c e s s o f a s a t u r a t e d s o l u t i o n o f sodium a c e t a t e
in w ater
was a d d e d . Upon c o o l i n g t h e s e m i c a r b a z o n e c r y s t a l l i z e d
e th y l alco h o l,
from w hich i t
from
s e p a r a t e s a s gleam ing y ello w
p la te s * A fter three c r y s ta lliz a tio n s
from e t h y l a l c p h o l ,
a s a m p l e was o b t a i n e d w h i c h was p u r e e n o u g h f o r a n a l y s i s .
M .P. 1 9 5 -1 9 7 ° .
C a l c d . f o r C^^H^ qN^O:
Found: 2 5 .9 5 , 2 6.41
N, 2 6 . 1 7
57-
Oxlme o f I s o q u i n a l d a l d e h y d e .
CH=NOH
A s o l u t i o n of 0 .2 5 g . of hydroxylam ine h y d r o c h l o r i d e
in a l i t t l e
w a t e r w as a d d e d t o a s o l u t i o n o f 0 . 5 g .
iso q u in ald ald eh y d e
of
i n a few c c . o f a n a l c o h o l and w a t e r
m i x t u r e . The s o l u t i o n was r e f l u x e d f o r f i v e t o t e n m i n u t e s
on a w a t e r b a t h . An e x c e s s o f a s a t u r a t e d s o l u t i o n o f
s o d iu m a c e t a t e was a d d e d , and t h e
s o lu tio n allow ed to
c o o l . The oxirae came dow n a s a w h i t e p o w d e r , w h i c h
recry stallized
be
f r o m a l c o h o l and w a t e r m i x t u r e s t o g i v e
s i l v e r y w h ite n e e d l e s , w hich under th e m ic ro sc o p e a p p e a r
to
be s m a l l r h o m b o i d s .
M .P. 1 7 1 - 1 7 2 ° .
A n a l . C a l c d . f o r C i 0 H8 N2 0 : Ni 1 6 . 2 7
F o u n d : N, 1 6 . 0 1
-58
Phenyl Hydrazone o f I s o q u i n a l d a l d e h y d e .
To a s o l u t i o n o f 0 . 5 g .
little
of is o q u in a ld a ld e h y d e in a
a l c o h o l w as a d d e d 0 . 5 g . o f p h e n y l h y d r a z i n e . The
s o l u t i o n was b o i l e d u n t i l t h e p h e n y l h y d r a z o n e
began t o
c r y s t a l l i z e , a n d t h e n a l l o w e d t o c o o l . The y i e l d o f p h e n y l
h y d r a z o n e a m o u n t e d t o d . 6 8 g , o r 83 % o f t h e
th eo retic al
y i e l d . The p h e n y l h y d r a z o n e c r y s t a l l i z e d f r o m e t h y l a l c o ­
hol in long y e llo w n e e d le s .
M .P. 1 7 4 - 1 7 5 ° .
A n a l . C a l c d . f o r C ^ H jjjN g : N, 1 7 . 0 0
F o u n d : N, 1 7 . 1 9
O i- N i t r o m e th y l - l is o q u in o l i n e M ethanol
AV«
To a m i x t u r e o f 0 . 3 g . o f n i t r o m e t h a n e a n d 0 . 3 2 g .
of i s o q u i n a l d a l d e h y d e was ad d ed
2
drops of d ie th y la m in e .
The s o l u t i o n became warm, i t w as c o o l e d a n d a l i t t l e
w ater
was a d d e d . The c o n d e n s a t i o n p r o d u c t s e p a r a t e d a s a n o i l
w h i c h c o u l d be made t o c r y s t a l l i z e
A f t e r d r y i n g on a p o r o u s t i l e ,
by v i g o r o u s s c r a t c h i n g .
t h e y i e l d was 0 . 2 9 g . o r
71 % o f t h e t h e o r e t i c a l y i e l d .
A ttem pts to c r y s t a l l i z e
t h i s compound f r o m e t h y l a l c o ­
h o l a n d w a t e r were u n s u c c e s f u l . I t may be c r y s t a l l i z e d
from l i g r o i n ,
but the m e ltin g p o in t a f t e r
l i z a t i o n was b r o a d e r a n d l o w e r .
M .P. 1 0 6 - 1 0 7 ° .
Analj^ C a l c d . f o r C^^H^QNgQ^* N, 1 2 . 8 4
F o u n d : N, 1 2 . 7 5
such a r e c r y s t a l ­
60
P -H ydroxy-P -l-isoquinolylpropiophenone
iw
J
ysJ-Cj
A few p i e c e s o f c r a c k e d i c e were added t o a s o l u t i o n
of
0 .2
g.
none i n
8
of iso q u in a ld a ld e h y d e and 0 .1 7 g .
c c . o f 95 % e t h y l a l c o h o l . F i f t e e n c c .
s o d iu m h y d r o x i d e
tu re
of a c e to p h e o f 10 %
s o l u t i o n was t h e n a d d e d s l o w l y . The m i x ­
was k e p t c o l d by a d d i a g s m a l l c h i p s o f i c e when
n e c e s s a r y . The s o l u t i o n s o o n became m i l k y a n d a f t e r 1 5 - 2 0
m i n u t e s a y e l l o w c r y s t a l l i n e p r o d u c t a p p e a r e d a n d was
filte re d
o f f . The p r o d u c t was w a s h e d w i t h a l i t t l e
h o l . The y i e l d a m o u n t e d t o 85 % o f t h e
T h i s k e t o n e w as s o l u b l e
soluble
tallized
th eo ry .
i n warm a l c o h o l ,
i n c o l d a l c o h o l , an d i n s o l u b l e
alco­
slig h tly
in w ater. I t cry s­
from a l c o h o l i n what a p p e a r e d t o
be n e e d l e s . U n d e r
a m i c r o s c o p e , h o w e v e r , t h e n e e d l e s w e r e s e e n t o be l i g h t
yellow p a r a lle le p ip e d s .
M .P. 1 1 4 . 5 - 1 1 5 ° .
A n a l . C a l c d . f o r C1 8 H1 5 N02 : N, 5 . 0 5
F o u n d : N, 4 . 7 6
A -l-Isoauinolffiicrylophenone V I I .
0
CH— CH-i
N
__
M e th o d A . I s o q u i n a l d a l d e h y d e
i n 15 c o .
( 0 . 2 5 g . ) was d i s s o l v e d
o f e t h y l a l c o h o l . To t h i s
e x c e ss of acetophenone (0 .3 8 g . ) ,
s o l u t i o n was a d d e d a n
and t h e n a l i t t l e
cracked
i c e . S i x c c . o f 10 % s o d iu m h y d r o x i d e s o l u t i o n were; a d d e d
slow ly w ith s u f f i c i e n t ic e
t o k e e p t h e m i x t u r e c o l d . The
r e a c t i o n m i x t u r e was t h e n a l l o w e d t o warm t o room t e m p e r a ­
t u r e a n d was a l l o w e d t o s t a n d f o r 60 m i n u t e s . A t t h e e n d
of th is
filte re d
tim e f i n e y e l l o w n e e d l e s had a p p e a r e d . They were
o f f and r e c r y s t a l l i z e d
f r o m e t h y l a l c o h o l . The
y i e l d a m o u n t e d t o 60 %•
M .P. 1 4 4 -1 4 6 °
M ethod B. E q u i m o l e c u l a r am ounts o f i s o q u i n a l d a l d e h y d e
(6 .5 g .)
2 cc.
and a c e to p h e n o n e
(0 .3 3 g . )
w er e d i s s o l v e d
in 1 to
of a b s o lu te a l c o h o l . Five d ro p s of a s o l u t i o n of
s o d iu m e t h y l a t d
i n a l c o h o l ( 0 . 0 5 g . o f s odiu m p e r c c . ) was
a d d e d . The r e a c t i o n m i x t u r e
became warm an d t u r n e d g r e e n .
A f t e r s t a n d i n g t h e s o l u t i o n bedame y e l l o w , a n d f i n a l l y
-62
so lid ified to a cry stallin e
mass* A f t e r a b o u t tw e n ty
m in u te s t h e c r y s t a l s were f i l t e r e d
o f f and washed t w i c e
w i t h a l c o h o l . The p r o d u c t ' o b t a i n e d i n t h i s m a n n e r was
colored,
b u t on b o n e b l a c k i n g a n d r e c r y s t a l l i z i n g f r o m e t h y l
a l c o h o l l i g h t y e l l o w n e e d l e s w e r e o b t a i n e d . The y i e l d
amounted t o 77 % o f th e t h e o r e t i c a l .
T h i s compound i s
so lu b le in e th y l a lc o h o l,
benzene,
and h o t l i g r o i n .
M .P. 1 4 5 . 5 - 1 4 6 ° .
A m i x e d m e l t i n g p o i n t o f t h e p r o d u c t s o b t a i n e d by
M e t h o d A a n d M e th o d B . showed n o d e p r e s s i o n . M i c r o s c o p i c
e x a m i n a t i o n o f t h e tw o s a m p l e s sh ow ed n o d i f f r e n c e ; b o t h
compounds a o p e a r e d t o c r y s t a l l i z e
in long p ris m s.
A n a l . C a l c d . f o r C 1 8 H1 3 NO: N, 5 . 4 0 ; C, 8 3 . 3 8 ; H,
5 .0 4 .
F o u n d : N, 5 . 5 0 ,
5.14,
5 . 4 4 ; C, 8 3 . 3 2 , 8 3 . 2 3 ; H,
4 .9 9 .
N o t e : I f t h e m o t h e r l i q u o r f r o m M e th o d A. was a l l o w e d
to stan d
0 .1 2
g.
of 3 - ( l- is o q u in o ly l) - l,5 - d ip h e n y l- l,5 - p e n -
t a n e d i o n e w as o b t a i n e d .
5 -(l-l3 o q u in o ly l)-1«5 -d ip h e n y l-l. 5 -pentanedione(V III.) .
W
An e x c e s s o f a c e t o p h e n o n e
aldehyde
( 0 .3 5 g . ) and i s o q u i n a l d ­
( 0 .2 5 g . ) were d i s s o l v e d
in 1 to 2 c e . of abso­
l u t e e t h y l a l c o h o l . One h a l f a c c . o f a s o l u t i o n o f s odiu m
ethylate
i n a l c o h o l ( 0 . 0 5 g . o f s o d i u m p e r c c . ) w as t h e n
added and th e r e a c t i o n v e s s e l s t o p p e r e d . A f t e r tw e n ty h o u rs
0 . 2 4 g . o f p r o d u c t was f i l t e r e d
42 % o f t h e
o f f . The y i e l d a m o u n t e d t o
theory.
This d ik e to n e c r y s t a l l i z e d
from a l c o h o l i n
b eau tifu l,
w hite p l a t e s . Under th e m ic ro s c o p e t h e s e p l a t e s a p p e a re d
r e c t a n g u l a r and s t r i a t e d a lo n g t h e i r s h o r t a x i s .
M .P . 1 3 3 - 1 3 3 . 5 ° .
A n a l . C a l c d . f o r CggHg^NOgi M o l e c u l a r w e i g h t 2 7 7 ;
N, 3 . 6 9 ; C, 8 0 . 9 0 ; H, 5 . 7 3 .
F o u n d : M o l e c u l a r w e i g h t 264} N, 3 . 6 8 ; 3 . 8 4 ; C
8 1 . 2 6 ; H, 5 . 5 7 .
N o t e ; T h i s co mpound w as a l s o p r e p a r e d by c o n d e n s a t i o n
of an e x c e s s of aceto p h en o n e
i n t h e p r e s e n c e o f NaOH.
°(-P h en y l-l-i8 o q .u irio lin eacry lo n itrile.
CN
CH=r C—
C
< >
O
M e th o d A i To a m i x t u r e
of 0 . 4 g .
of ph en y l a c e t o n i r i l e
an d 0 . 5 g . o f i s o q u i n a l d a l d e h y d e was a d d e d s u f f i c i e n t a b s o ­
l u t e a l c o h o l t o make a c l e a r s o l u t i o n ( 0 . 5 c c . ) . A f e w c r o p s
o f d i e t h y l a m i n e were a d d e d a n d t h e m i x t u r e a l l o w e d t o
o v ern ig h t. D ilu te
tio n
s o d iu m h y d r o x i d e was a d d e d a n d t h e
stand
so lu ­
b r o u g h t t o a b o i l . S u f f i c i e n t a l c o h o l was a d d e d t o t h e
b o i l i n g m i x t u r e t o make a c l e a r s o l u t i o n ,
and t h e s o l u t i o n
was t h e n a l l o w e d t o c o o l . L i g h t y e l l o w n e e d l e s s e p a r a t e d
w h i c h became c o l o r l e s s on r e c r y s t a l l i z a t i o n f r o m e t h y l a l c o ­
h o l . The y i e l d was 0 . 4 8 g . o r 57 % o f t h e
theory.
M .P. 9 6 - 9 7 ° .
M e t h o d B . - A. s o l u t i o n o f 0 . 5 g o f i s o q u i n a l d a l d e h y d e
and 0 . 4 g .
of phenyl a c e t o n i t r i l e i n 1 c c .
of a b s o lu te
a l c o h o l was t r e a t e d w i t h 3 d r o p s o f s o d i u m e t h y l a t e
( 0 . 0 5 g . o f s o d iu m p e r c c . ) . The s o l u t i o n
so lu tio n
became warm, a n d
c o l o r e d . . U p o g c o o l i n g a n d s c r a t c h i n g et w h i t e
cry stallin e
-6 5 \
s o l i d w a s o b t a i n e d . The y i e l d a m o u n t e d t o 0 . 7 5 g . o r 9 2 ^
o f t h e t h e o r y . T h i s compound was p u r i f i e d
by r e c r y s t a l l i z a ­
t i o n from e t h y l a l c o h o l .
M .P. 9 6 . 5 - 9 7 ° .
A m i x e d m e l t i n g p o i n t w i t h t h e p r o d u c t fro m M e th o d
A. showed no m e l t i n g p o i n t d e p r e s s i o n . M ic r o s c o p i c e x a m in a ­
t i o n sh ow ed n o d i f f r e n c e
T h i s compound i s
i n cold a lc o h o l,
in c ry s ta l s tr u c tu r e .
in so lu b le in w ater, d i f f i c u l t l y
and s o l u b l e
in hot a lc o h o l. In alcohol
s o lu t io n the 4 - p h e n y l - l - i s o q u i n o l i n e a c r y l o n it r i l e
intense
so lu b le
gave an
red w ith c o n c e n tra te d h y d ro ch lo ric a c id .
A n a l . C a l c d . f o r C^gHigNg: N, 1 0 . 9 3 ; C , 8 4 . 3 6 ;
H, 5 . 1 3 .
F o u n d ; N, 1 0 . 9 4 ; C , 8 4 . 4 4 ; H, 4 . 8 3
-6 6
* -P h e n y l-? -h y d ro x y -l-is o g u in o lin e p ro p io n ic acd, E th y l E s te r
g
C - 0 -CgH5
o
CHOH-CH
I
N
W
A s o lu tio n of 0 .5 g .
o f i s o q u i n a l d a l d e h y d e w as made
w i t h 4 c c . o f a b s o l u t e a l c o h o l an d 0 . 5 g . o f e t h y l p h e n y l a c e t a t e . T h i s s o l u t i o n w as c o o l e d i n a n i c e
i t was ad d e d a l i t t l e
s o d iu m e t h y l a t e
b ath and to o
s o lu tio n (5 t o 8
d r o p s o f a s o l u t i o n c o n t a i n i n g 0 . 0 5 g . o f s o d iu m p e r c c . ) .
The m i x t u r e
then
slow ly changed c o l o r ,
first
becoming b l u e a n d
b l u i s h - g r e e n . A f t e r a n h o u r t h e m i x t u r e was a l l o w e d
t o warm up t o room t e m p e r a t u r e .
It
s o o n became y e l l o w and
b e g a n t o c r y s t a l l i z e . A f t e r s t a n d i n g f o r a n h o u r a t room
tem perature
it
was c o o l e d a g a i n a n d t h e w h i t e c r y s t a l l i n e
n e e d l e s were f i l t e r e d
o f f . The y i e l d a m o u n t e d t o 0 . 3 8 g .
o r 4 5 % o f t h e t h e o r y . On r e c r y s t a l l i z a t i o n f ro m e t h y l
alco h o l,
solu b le
b e a u t i f u l w h i t e n e e d l e s were o b t a i n e d w h i c h w er e
in alcohol,
but in s o lu b le
in w ater.
M .P. 1 3 4 . 5 - 1 3 5 . 5 ° .
A n a l . C a l c d . f o r CgoH^gNOg: N, 4 . 3 6 ; C, 7 4 . 7 2 ;
H, 5 . 9 8 .
F o u n d : N, 4 . 4 7 ; C , 7 4 . 4 6 ; H, 5 . 6 1 .
-67
3-M ethyl-6.7-m eth.ylenedioxy iso q u in a ld a ld e h y d e
(III.)
CHO
0
-
0
-
-CH
To a s o l u t i o n o f 2 . 2 g . o f 1 , 3 - d i m e t h y l - 6 , 7 - m e t h y l e n e d ioxyisoquinoline
of 1 .3 g .
in
20
c c . o f d i o x a n e was a d d e d a s o l u t i o n
o f s e l e n i u m d i o x i d e d i s s o l v e d i n 20 c c .
containing a l i t t l e
of dioxane
w a t e r . The s e l e n i u m d i o x i d e s o l u t i o n
was a d d e d d r o p by d r o p w i t h c o n s t a n t m e c h a n i c a l s t i r r i n g
du rin g the
c o u r s e o f one h a l f a n h o u r . D u r i n g t h e a d d i t i o n
t h e r e a c t i o n m i x t u r e was warmed g e n t l y on a w a t e r b a t h .
At f i r s t a w h i t e
so lid separated,
but a s the r e a c tio n con­
t i n u e d t h i s w e n t i n t o s o l u t i o n . H e a t i n g was c o n t i n u e d f o r
a n h o u r a n d a h a l f on a s t e a m
b a t h . The s e l e n i u m was f i l ­
t e r e d from t h e h o t s o l u t i o n and t h e m i x t u r e steam d i s t i l l e d .
When t h e
b u lk o f th e d io x an e had been d i s t i l l e d ,
hyde began t o s o l i d i f y i n t h e
A fter c o o lin g ,
the a ld e ­
steam d i s t i l l a t i o n f l a s k .
t h e a l d e h y d e w as f i l t e r e d
o f f and d r i e d a t
room t e m p e r a t u r e . The y i e l d o f p u r e a l d e h y d e , a f t e r r e c r y s tallizin g
f r o m t o l u e n e a m o u n t e d t o 0 . 8 0 g . o r 34 % o f
68-
the th e o ry .
The 3 - r a e t h y l - 6 , 7 - m e t h y l e n e d i o x y i s o q u i n a l d a l d e h y d e
reduces T ollen*s re a g e n t producing s i l v e r .
in hot eth y l a lc o h o l, hot to lu e n e ,
-The a l d e h y d e
is
insoluble
It
is
so lu b le
d i o x a n e , an d p y r i d i n e .
in w ater, d i f f i c u l t l y
soluble
i n cold a l c o h o l . B e a u tif u l l i g h t y e llo w n e e d le s a re
tain ed
ob­
by r e c r y s t a l l i z a t i o n f r o m e t h y l a l c o h o l .
M .P. 1 8 6 . 5 - 1 8 8 . 5 ° •
A n a l . C a l c d . f o r C^gHgNOg: N, 6 . 5 1
F o u n d : N, 6 . 6 4
N o t e . On e v a p o r a t i o n o f t h e f i l t r a t e
o f f th e crude a ld e h y d e , a re d b a s ic
w h i c h was n o t f u r t h e r i n v e s t i g a t e d .
after filte rin g
compound was o h t a i n e d
-6 9 -
Oxime o f 3 - M e t h y l - 6 >7 - m e t h y l e n e d i o x y i s o q u i n a l d a l d e h y d e .
CH —NOH
A s o l u t i o n o f 0 .1 g . of hydroxylam ine h y d r o c h lo rid e
i n 0 . 5 c c . o f w a t e r w as a d d e d t o a s u s p e n s i o n o f 0 . 1 4
grams o f th e a ld e h y d e
i n 4 c c . o f h o t a l c o h o l . The r e a c t i o n
m i x t u r e was r e f l u x e d f o r one h o u r o n a w a t e r b a t h , an d t h e n
made n e u t r a l t o c o n g o p a p e r by a d d i n g a s a t u r a t e d s o l u t i o n
o f s o d iu m a c e t a t e . A f t e r c h i l l i n g
filtered
in ic e ,
the
o f f . The y i e l d a m o u n t e d t o 0 . 1 3 g .
The oxime was s o l u b l e
oxime was
o r 87 %.
in an excess of acid or base. I t
c r y s t a l l i z e d from a n a l c o h o l and w a te r m ix tu r e i n v ery
sm all n e e d le s .
M .P . 2 1 5 - 2 1 6 ° .
A n a l . C a l c d . f o r C 1 2 H1 0 N2 O3 : N, 1 2 . 1 7
Found: N 11.80,
11.90
■
70
V -.P henyl-ft-(3-m ethyl-6.7-m eth ylenedioxy-l-isoqu in olyl )a cry lo n itrlle•
CN
To a s u s p e n s i o n o f 0 . 1 g .
dioxyisoquinaldaldehyde
in
of 3 -m e th y l-6 ,7 -m eth y len ecc.
2
of ab solute
a l c o h o l was
added 0 .3 g . of phenyl a c e t o n i t r i l e . A f t e r ad d in g 3 d ro p s
o f NaOEt s o l u t i o n
( 0 . 0 5 g . o f sodium p e r c c . o f a l c o h o l ) ,
t h e s o l u t i o n was r e f l u x e d f o r 5 h o u r s . A l i t t l e
added to the ho t s o l u t i o n ,
and i t
c r y s t a l l i n e p r o d u c t was f i l t e r e d
w a t e r was
w as a l l o w e d t o c o o l . The
o f f and r e c r y s t a l l i z e d
from
e th y l alco h o l.
M.P. 1 6 3 . 5 - 1 6 5 ° .
A n a l . C a l c d . f o r C ^ g l ^ g N g O g : N, 9 . 8 5
F o u n d : Nf 9 . 3 0 .
Note, .
C o n d e n s a t i o n i n d i o x a n e and e t h y l c e l l o s o l v e
i n th e co ld o v e r n i g h t gave no r e a c t i o n . A f t e r tw e lv e t o
tw enty fo u r hours s ta n d in g ,
the
c o u l d be r e c o v e r e d u n c h a n g e d .
bulk of th e
s ta r tin g m aterial
-71-
3-M ethyl-6,7-dim ethoxyisoquinaldaldehyde
(IV .)
CHO
GHc
ch3 - ° -
1,3 -D im ethy1 - 6 , 7 -d im e th o x y iso q u in o lin e
o x id iz e d w ith 1 .3 g . of selenium d io x id e
i d e n t i c a l w ith t h a t used f o r
iso^quinolinfi
1
(1 .8 g .)
was
by a p r o c e d u r e
,3 -d im e th y l-6 ,7 -ra e th y le n e d io x y -
( p a g e 6 7 ) . The i s o l a t i o n a n d p u r i f i c a t i o n
of
t h i s a ld e h y d e , how ever, proved d i f f i c u l t . A f t e r rem oving
the dioxane
by s t e a m d i s t i l l a t i o n
T h i s s o l i d was p u r i f i e d
tatin g
it
w ith d ilu te
cry stallized
0 .8
by d i s s o l v i n g
g . of s o lid rem ained.
i n a c i d and p r e c i p i ­
s o d iu m h y d r o x i d e . T h i s was t h e n r e ­
fro m l i g r o i n .
M .P. 1 5 0 .5 - 1 5 2 ° w i t h d e c o m p o s i t i o n .
A n a l . C & lc d . f o r C ^ H ^ N C s : N , 6 . 0 6
Found: V, 5 .9 9 .
N o te.
When t h i s p r o c e d u r e was r e p e a t e d on s m a l l e r
am ounts o f d i m e t h y l i s o q u i n o l i n e , no s o l i d rem ained a f t e r
d istillin g
o f f t h e d i o x a n e . By a d d i n g a n e x c e s s o f s o d iu m
h y d r o x i d e t o t h e m o t h e r l i q u o r a n o i l was o b t a i n e d w h i c h
could
be c r y s t a l l i z e d
by l a y e r i n g w i t h p e t r o l e u m e t h e r .
T h i s s o l i d was d i f f i c u l t
to p u r if y .
N o t e . The a l d e h y d e ( m . p . 1 5 0 . 5 - 1 5 2 ° )
m .p. 1 8 2 -1 8 5 °.
f o r m s a n oxime
72-
APPENDIX.
A b r i e f d i s c u s s i o n o f some o f t h e w o r k w h i c h w as done
in connection w ith t h i s re s e a r c h w ith n e g a tiv e r e s u l t s
is
g iv e n in the fo llo w in g p a ra g ra p h s .
A. A t t e m p t s t o p r e p a r e c ( - p h e n y l e t h a n o l a m i n e .
1
. N itr o m e th a n e was c o n d e n s e d w i t h b e n z a ld e h y d e
i n t h e p r e s e n c e o f s o d iu m m e t h y l a t e
u s e d by
H o lle m a n ^ .
The s o d i u m s a l t w h i c h r e s u l t e d w as d e ­
co m p o se d w i t h a c e t i c
m ethylm ethanol ( I . )
a c c o r d i n g t o a m e th o d
a c i d , a n d a n 80 % y i e l d
of p h e n y ln itro -
w as o b t a i n e d . A t t e m p t s w e r e made t o r e ­
d u c e t h i s compound t o t h e a m i n e ,
b u t none w ere s u c c e s f u l .
choh-ch2 -no2
I
I.
A w hite c r y s t a l l i n e
co mpound (m .p# 1 5 8 ° ) w a s o b t a i n e d
th e r e d u c t i o n of I . w ith h y d ro g en in th e p r e s e n c e
of Raney
n i c k e l . T h i s compound was n o t f u r t h e r i n v e s t i g a t e d ;
n o t the d e s ir e d am ine. I .
ch lo rid e
by
i t was
was a l s o r e d u c e d w i t h s t a n n o u s
and h y d r o c h l o r i c a c i d ,
b u t once a g a i n n o e t h a n o l -
a m i n e was r e c o v e r e d . I n t h i s c a s e a 70 % y i e l d o f t h e oxime
of p h en y lacetald eh y d e
8
(II.)
w as o b t a i n e d .
. I s o n i t r o s o a c e t o p h e n o n e was p r e p a r e d by t h e m e th o d
73-
ch2-ch = n o h
I
/s
II.
of C l a i s e n 5 0 . A ttem pts to reduce t h i s
compound c a t a l y t i c a l l y
w i t h p a l l a d i u m o r p l a t i n u m b l a c k w e r e u n s u c c e s f u l . T h i s com­
p o u n d w as r e d u c e d w i t h s t a n n o u s c h l o r i d e
a c id to give
This s a l t
tio n ,
the t i n double s a l t
and h y d r o c h l o r i c
of tt-am inoacetophenone •
c a n n o t be d e c o m p o s e d by s o d iu m h y d r o x i d e s o l u ­
f o r the f re e keto-am ine
i s n o t s t a b l e . The d o u b l e
s a l t was d e c o m p o s e d w i t h h y d r o g e n s u l f i d e . A t t e m p t s w e r e
made t o r e d u c e t h i s compound w i t h p a l l a d i u m
and w ith p la tin u m b la c k ,
is p o ssib le
on c h a r c o a l
but r e d u c t i o n did n o t p ro c e e d .
that e ith e r su lfid e s or t i n
salts
It
contam inated
t h e amine h y d r o c h l o r i d e and p o i s o n e d t h e C a t a l y s t s .
- A m i n o a c e t o p h e n o n e h y d r o c h l o r i d e was a c e t y l a t e d w i t h
a c e t i c a n h y d r i d e a n d s odiu m b i c a r b o n a t e ,
but the N - a c e ty l-
- a m i n o a c e t o p h e n o n e was n o t e a s y t o p u r i f y .
c r y s t a l l i z e d f ro m b e n z e n e ,
I t c o u l d be r e ­
b u t o n ly a f t e r most of th e
ben­
zene had e v a p o r a t e d . Such a p u r i f i c a t i o n d i d n o t g iv e a
compound s u f f i c i e n t l y p u r e t o w a r r a n t a t t e m p t s a t c a t a l y t i c
red u ctio n .
3.
Benzoyl cyanide
acetophenone w ith a c e t y l c h lo r id e
(III.)
was p r e p a r e d by t r e a t i n g
and i s o a m y l n i t r i t e . T his
method was d e v e l o p e d by C l a i s e n ^ l . T h i s compound was p u r i -
CO-CN
III.
fied
by vacuum d i s t i l l a t i o n . R e d u c t i o n a t t e m p t s w i t h p a l ­
l a d i u m on c h a r c o a l w e r e u n s u c c e s f u l . The h y d r o g e n p r e s s u r e
began to d ro p a t f i r s t ,
b u t a f t e r a b o u t one t h i r d
th e o r e tic a l pressure drop,
of the
the r e a c t i o n s to p p e d .
B. A t t e m p t s t o p r e p a r e 1 - m e t h y l i s o q u i n o M n e .
1.
l-;2 -D im eth y l-l,2 -d ih y d ro iso q u in o lin e
(IV .)
w as p r e p a r e d by t h e a c t i o n o f m e t h y l m a g n e s iu m i o d i d e
on t h e m e t h i o d i d e
o f i s o q u i n o l i n e . F r e u n d a n d Bode
used t h i s method f o r th e p r e p a r a t i o n o f t h i s
a number o f o t h e r
1
52
have
compoun d and
, 2 -d ih y d ro iso q u in o lin es.
IV.
A ttem pts to
oxidize t h i s
peroxide in d i l u t e
in d ilu te
su lfu ric
s u lfu ric acid ,
compound w e r e m a d e . H y d r o g e n
a c id , p otassium perm anganate
and s e le n iu m d i o x i d e w ere t r i e d .
-75-
In each case o x id a tio n o c c u rre d w ith the e v o lu tio n of a
g a s w h i c h was i d e n t i f i e d a s c a r b o n d i o x i d e by b u b b l i n g i t
th r o u g h lim e w a t e r . I n no c a s e , how ever, co u ld any 1 - m e th y lisoquinoline
be o b t a i n e d .
C . A t t e m p t e d S t e p h e n ' s r e d u c t i o n on 1 - c y a n o i s o q u i n o l i n e .
1 . R eissert5 3 has
show n t h a t
iso q u in o lin e
reacts
w i t h b e n z o y l c h l o r i d e a n d s o d iu m c y a n i d e t o g i v e a n a d d i ­
t i o n compound ( V . ) , w h i c h d e c o m p o s e s on f u s i o n w i t h p h o s ­
phorus p e n ta c h lo rid e
to give i-c y an o iso q u in o lin e
(V I.).
CN
w
W
V.
VI.
1 - C y a n o i s o q u i n o l i n e was p r e p a r e d and a n a t t e m p t was
made t o r e d u c e
i t w ith stannous c h lo r id e ,
hydrogen c h l o r id e ,
a n d e t h e r . By s u c h a r e d u c t i o n S t e p h e n h a s o b t a i n e d a
number o f a l d e h y d e s from th e
c o r r e s p o n d i n g n i t r i l e s . When
s u c h a r e d u c t i o n was a t t e m p t e d , h o w e v e r , a co m pound w h i c h
was v e r y i n s o l u b l e
i n e t h e r was p r o d u c e d . T h i s co mpound
d e c o m p o s e d on t r e a t m e n t w i t h w a t e r t o g i v e t h e
n itrile ,
and i t
i s p ro b a b ly the h y d ro c h lo rid e
iso q u in o lin e.
D. C o n d e n s a t i o n s o f 1 - m e t h y l i s o q u i n o l i n e .
o rig in al
of
1
-cyano-
76-
A t t e m p t s w e r e made t o c o n d e n s e 1 - m e t h y l i s o q u i n o l i n e
w ith b e n z o y lfo rm a n ilid e
i t occurred,
produce th e
woul g iv e
( V I I . ) . Such a c o n d e n s a tio n ,
(V III.)
if
w h i c h on h y d r o l y s i s s h o u l d
same compound a s h y d r o l y s i s o f
K -phenyl-1 -
i s o q u i n o l i n e a c r y l o n i t r i l e would g i v e . T h i s c o n d e n s a t i o n
did n o t p r o c e e d , a lth o u g h a v a r i e t y o f co n d en sin g a g e n ts
wer e t r i e d . D i e t h y l a m i n e , s o d i u m e t h y l a t e ,
chlo rid e
i n l i g r o i n were a l l
tried .
f o r m a n i l i d e c o u l d be i s o l a t e d ,
a n d alum inum
In each case benzoyl-
b u t no c o n d e n s a t i o n p r o d u c t
was f o u n d .
C o n d e n sa tio n s o f 1 -m e th y lis o q u in o lin e w ith arom atic
a l d e h y d e s d i d o c c u r . The y i e l d s , h o w e v e r , w e r e l o w , an d
the c o n d e n s a tio n s d i f f i c u l t ,
t h e w o r k was a b a n d o n e d .
0
0
II
II
c—- c
V it
\
VIII
and t h e r e f o r e
t h i s phase
of
-77
SUMMARY.
1 . A new m e th o d f o r d e h y d r o g e n a t i o n h a s
been s u g g e s t e d .
U sing Raney n i c k e l as th e c a t a l y s t l - m e t h y l - 3 , 4 - d i h y d r o i s o q u i n o l i n e has been d e h y d ro g e n a te d t o
1-m
e th y liso q u in o ­
lin e •
2 . The m e l t i n g p o i n t s o f s e v e r a l o f t h e c r y s t a l l i n e
d eriv ativ e s of
1-m
M elting p o in ts fiv e
e th y l i s o q u i n o l in e have been c o r r e c t e d .
to t h i r t y d e g re e s h ig h e r than those
p r e v i o u s l y r e p o r t e d h a v e b e e n f o u n d f o r some o f t h e s e
d eriv ativ e s.
3 . T h r e e new a l d e h y d e s h a v e
teriz ed ,
i.e .
been p r e p a r e d and c h a r a c ­
iso q u in a ld a ld e h y d e , 3 -m e th y l-6 ,7 -m eth y len e-
d io x y is o q u in a ld a ld e h y d e , and 3 -m e th y l-6 ,7 -d im e th o x y iso quinaldaldehyde.
4 . The u s e o f s u c h a l d e h y d e s i n s y n t h e s i s h a s b e e n
dem onstrated
active
by c o n d e n s a t i o n o f i s o q u i n a l d a l d e h y d e w i t h
" m e t h y l e n e " c o m poun ds s u c h a s p h e n y l a c e t o n i t r i l e
and e t h y l p h e n y l a c e t a t e .
5. Evidence in s u p p o rt of th e g e n e r a l l y a c c e p te d th e o r y
of c o n d e n s a t i o n s h a s been o f f e r e d ,
o f t h e p r o d u c t s w h i c h may r e s u l t
by t h e
iso latio n
of a l l
from a c o n d e n s a t i o n of
i s o q u i n a l d a l d e h y d e and a c e t o p h e n o n e .
-78
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