Synthesis of some new analogs of thyroxine

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Content SYNTHESIS OP SOME NEW ANALOGS OP THYROXINE
fey
J o h n C hih-A n Hu
A T h e s is P r e s e n t e d t o th e
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
I n P a r t i a l F u l f i l l m e n t o f th e
R e q u ire m e n ts f o r th e D e g ree
MASTER OF SCIENCE
(C h e m is try )
Ju n e 1957
U M I Number: EP41612
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U N IV E R SIT Y O F S O U T H E R N C A L IF O R N IA
GRADUATE SC H O O L
U N IV ER SITY PA R K
L O S A N G E L E S 7
C . '5 7 14 8 7 +
This thesis, written by
John QM^An..B“
under the guidance of h-i&...Faculty Committee,
and approved by all its members, has been pre
sented to and accepted by the Faculty of the
Graduate School, in partial fulfillment of the
requirements for the degree of
M aster o f Science
John D. Cooke
Acting Dean
D a te......................... ...........................................................
Faculty Com m ittee
Chairman
. . . W i i .
acknowledgments
The a u th o r w is h e s t o e x p r e s s h i s a p p r e c i a t i o n t o
D r. Norman K h a ra s c h f o r h i s c o n s t a n t g u id a n c e an d
e n c o u ra g e m e n t i n c a r r y i n g o u t t h e s e i n v e s t i g a t i o n s and i n
th e w r i t i n g o f t h i s t h e s i s . The a s s i s t a n c e o f th e P u b l i c
H e a lth S e r v i c e i n p r o v i d i n g a f e l l o w s h i p g r a n t i s a l s o
g r a t e f u l l y a c k n o w le d g e d .
TABLE GP CONTENTS
C h a p te r
I . INTRODUCTION . . . . . ..............................................................
1 . H i s t o r y a n d Im p o rta n c e o f T h y ro x in e a s
a Hormone •. • . . .. • • ...............................
2* Some C o n s i d e r a t i o n s A bout th e R e l a t i o n s
o f S t r u c t u r e a n d P h y s i o l o g i c a l A c t i v i t y
o f T h y ro x in e an d i t s A n alo g s . . . . . .
3- P u r p o s e s o f t h i s I n v e s t i g a t i o n .....................
I I . THE "GLAZO-MODIFICATION" OP THE ULLMANN-NADAI
REACTION . . . . . ... . . . . . . . ... . . . . . . .
i • . . . . . . .
I I I I . DISCUSSION OF EXPERIMENTAL W O R K ............................... .....
A. S t u d i e s Toward t h e S y n t h e s i s o f th e S u l f u r
A n alo g s o f T h y ro x in e an d D e s a m in o th y ro x in e .
1 . The S u l f u r A nalog o f D e s a m in o th y ro x in e .
2® R e s u l t s Toward th e S y n t h e s i s o f th e
S u l f u r A n alo g o f T h y ro x in e . . . . . . .
3 . The R e s u l t s o f A tte m p ts t o E f f e c t a New
S y n t h e s i s o f p -M e th o x y th io p h e n o l . . . .
B. S t u d i e s Tow ard th e S y n t h e s i s o f T h y ro x in e
A n alo g s w i t h B ulky G roups i n t h e 3 1,5
P o s i t i o n s o f t h e Prim e R in g .....................
C« R e s u l t s o f A tte m p ts t o S y n t h e s i z e T h y ro x in e
by th e M ethod o f H i l l m a n ......................... . . . .
IV . EXPERIMENTAL . . . . '...................................................................
1 . p -H y d ro x y h y d ro c in n a m ic A c i d ..........................
2 . 3 ,5 - D in itr o - 4 - h y d r o x y h y d r o c i n n a m i c A c id .
Page
1
1
2
5
8
I
111
I
f
1 1
11
16
18
21
26
3 !
31
32
C h a p te r
i
i v
Page
3 . E t h y l 3 , 5 - B i h i t r o - 4 - l : y
h y d r o x y h y d r o c i nnama t e
4 . p -M e th o x y th io p h e n o l .
5«
6.
7 •
E t h y l 3 , 5 - D i n i t r o - 4 -
(p-me th o x y th io p h e n o x y ) -h y d r o c in n a m a te
E t h y l 3 ,5 - D i i o d o - 4 -
( p -m e th o x y th io p h e n o x y )- h y d ro c in n a m a te
3 , 5 - D i i o d o - 4 - (p -m e th o x y th io p h e n o x y ) -
h y d ro c in n a m ic A c id . • .
• • •
8 * T re a tm e n t o f E th y l 3 ,5 - D i i o d o - 4 -
( p-me th o x y th io p h e h o x y )- h y d r o c in n a m a te
w ith H y d r io d ie a n d A c e t i c A c id s . .
9 . 3 , 5 - D i n l t r o - L - t y r o s i n e . . . .
1 0 • 3 , 5 - D i n i t r o - N - a e e t y l - L - t y r o s i n e
1 1 .
12.
1 3 .
E t h y l 3 , 5 - B i n l t r o - N - a c e t y l - L -
t y r o s i n a t e • • • ..................... .....
3 , 5 - D i n i t r 0 - 4 - (p-me th o x y th io p h en o x y ;) iK -
a c e t y l - L - a l a n i n e E th y l E s t e r . . . .
2 ,4 - D i n i t r o p h e n y l p -M e th o x y p h e n y l
S u l f i d e . .
1 4 . An A tte m p te d S y n t h e s i s o f
p - M e th o x y th io p h e n o l hy C le a v a g e o f
2 , 4 - B i n i t r o p h e n y l p -M e th o x y p h e n y l
S u l f i d e ... .. ....................................
1 5 . 2 , 6 - B i i s o p r o p y l - 4 - n i t r o s o p h e n o l
1 6 . 2 ,6 - B i is o p r o p y l- 4 - h y d r o x y p h e n o l
1 7 . E t h y l 3 , 5 - d i n i t r o - 4 - ( 3 1 , 5 1- d i i s o p r o p y l -
4 ' - h y d r oxyphe n o x y ) -h y d ro c innam a t e
1 8 . 4 , 4 * -D im e th o x y d ip h e n y lio d o n iu m I o d id e
1 9 . 3 , 5 - D i i o d o - L - t y r o s i n e . . . .
2 0 . 3 , 5 - D i i o d o - N - a c e t y l - L - t y r o s i n e
• • •
V
C h a p te r Page
2 1 . 3 , 5 - D i i o d o - N - a c e t y l - L - t y r o s i n e E th y l
E s t e r . . . . . . . . . . .*. . . . . 4 5
2 2 . 3 ,5 -D iio d o -4 ~ p -m e th o x y p h e n o x y -N -
a c e t y l - L - t y r o s i n e ............................... . . . 45
2 3 . 3 ,5 - D i i o d o - L - t h y r o n in e ....................... 46
BIBLIOGRAPHY . . . . . . . . . . .............................................. 4 7
CHAPTER I
INTRODUCTION
1 . H i s t o r y a n d Im p o rta n c e o f T hyrox i n e a s a
horm one. - - I n t h e s o u t h w e s t e r n p a r t o f C h in a , some p e o p le who
l i v e d i n th e m o u n ta in s w ere o f t e n a f f l i c t e d w i t h tu m o rs on
jthe t h r o a t , i . e . g o i t e r . I t i s s a i d t h a t a b o u t f i v e
jth o u san d y e a r s ag o t h i s d i s e a s e was fo u n d t o be c u r e d o r
p r e v e n t e d w ith b u r n t sp o n g e o r co o k ed se aw ee d b y ; th e C h in e se
I
Sm peror SHEN NUNG ( 3 7 ) , who was th e f o u n d e r o f C h in e se
m e d ic in e an d a g r i c u l t u r e . T h is rem edy was d e s c r i b e d i n
pPEN-T^AO KANG-MU,” a c o m p re h e n s iv e e n c y c l o p e d i a , o r th e
! *
’ ’B e i l s t e i n H andbuch” o f C h in e s e m e d i c i n e , w h ic h was e d i t e d
jand p u b l i s h e d i n 1597 ( 1 , 3 9 , 49) • T h is rem edy h a s b e e n
p e e d fro m g e n e r a t i o n t o g e n e r a t i o n f o r th o u s a n d s o f y e a r s ,
b u t n o t h in g h a s b e e n known a b o u t t h e c h e m is tr y o f t h i s
t h e r a p e u t i c a l f u n c t i o n u n t i l th e r e s u l t s o f r e c e n t r e s e a r c h
became a v a i l a b l e . C h e m ic a l a n a l y s i s r e v e a l e d t h a t a l l th e
m e d i c i n a l a lg a e d e s c r i b e d i n th e PEN-T’SAO h a n d b o o k , h a d a
y e ry h i g h i o d i n e c o n t e n t ( 1 , 4 9 ) . I n 1 8 9 5 , Baumann
i i s c o v e r e d io d in e a s a n e s s e n t i a l com ponent o f t h e t h y r o i d
g la n d ( 5 ) ; and i n 1 9 1 4 , K e n d a ll f i r s t i s o l a t e d a c h e m ic a l
com pound, t h y r o x i n e , a s th e r a c e m a te , fro m th e t h y r o i d
s x t r a c t ( 3 2 ) , b u t was u n a b le t o a r r i v e a t th e c o r r e c t
2
s t r u c t u r e f o r i t .
The c h e m ic a l s t r u c t u r e ( I ) a n d s y n t h e s i s
I I
CH2 GH-G0GH
of t h y r o x i n e w ere e l a b o r a t e d by H a r in g to n i n 1926 ( 2 5 ) .
S in ce t h e n t h y r o x i n e h a s b e e n c o n s i d e r e d a s a n i m p o r t a n t
com ponent o f t h y r o i d h o rm o n e. M odern r e s e a r c h w o rk e rs
p r o v e d t h a t t h i s horm one i s f u l l y a s im p o r ta n t
p h y s i o l o g i c a l l y a s t h e p i t u i t a r y h o rm o n e s . As h a s b e e n s a i d
by C u s h in g , t o h i s m e d ic a l s t u d e n t s a t H a r v a r d , wi f t h e
p i t u i t a r y i s v ie w e d a s th e l e a d e r o f t h e e n d o c r in e
o r c h e s t r a , p e rh a p s th e t h y r o i d may b e r e g a r d e d a s t h e f i r s t
v i o l i n ” ( 4 7 ) . I n th e p a s t few y e a r s , a l s o ,
t r i ^ l o d o t h y r o n i n e (2 4 ) h a s g a in e d im p o r ta n c e .
2* Some c o n s i d e r a t i o n s a b o u t th e r e l a t i o n o f
s t r u c t u r e a n d p h y s i o l o g i c a l a c t i v i t y o f T h y ro x in e and i t s
ia n a lo g s . —■ P h y s i o lo g i c a l ly , t h y r o x i n e i s o f maximum
im p o r t a n c e ,. y e t c h e m i c a l l y , i t h a s a c o m p a r a tiv e ly s im p le
s t r u c t u r e * I t t h e r e f o r e seem s p o s s i b l e t o f i n d i n f o r m a t i o n
o f fu n d a m e n ta l s i g n i f i c a n c e by s t u d y i n g t h i s i m p o r t a n t , y e t
s t r u c t u r a l l y s im p le h o rm o n e. Much i n t e r e s t h a s b e e n
r e c e n t l y re a w a k e n e d among c h e m is ts a n d b i o c h e m i s t s
3
c o n c e r n in g th e m ech anism o f th e a c t i o n o f t h y r o i d horm one
b h y ro x in e a n d i t s p h y s i o l o g i c a l a c t i v i t y .
K e n d a ll i n h i s e a r l y r e v ie w o f t h y r o i d h o rm o n e,
s o n s id e r e d t h a t t h e p h y s i o l o g i c a l r e s p o n s e s b r o u g h t a b o u t by
b h y ro x in e w ere a s s o c i a t e d w i t h i t s p a r t i c i p a t i o n i n a n
o x id a tiv e , r e a c t i o n ( 3 3 ) . Niemann fo u n d t h a t th e
o r t h o r is o m e r ( I I ) o f t h y r o x i n e show ed lo w e r t h y r o x i n e
I n a c t i v e . B ased u p o n t h i s o b s e r v a t i o n and o t h e r r e a s o n s , he
s u g g e s te d th e n e c e s s i t y o f a p o t e n t i a l q u l n o id s t r u c t u r e f o r
bhe com pound, t o show p h y s i o l o g i c a l a c t i v i t y , b e c a u s e b o t h
b h y ro x in e ( I ) a n d i t s o r th o « is o m e r ( I I ) c o u ld h av e th e
and th e c o r r e l a t i o n s b e tw e e n t h e c h e m ic a l c o n s t i t u t i o n o f
CHgCHCOOH
NHg
CH2 CHC00H
I OH I H0 I I
I I I I I
a c t i v i t y i n th e r a t , w h e re a s t h e m e ta - is o m e r ( I I I ) was
f o l lo w in g r e d o x e q u i l i b r i a ,
HO .-CHgCHCOOH
nh 2
^ S - Q - G H g C H G O O H * H* -» 2 e
I I - A w • . • ' ,
I I
O “D~0 “ CH2 < rHCOOH
I I
O -0> ~C H 2CHCOOH * H* ♦ 2e
__I
[but t h e m e ta - is o m e r ( I I I ) s h o u ld be i n c a p a b l e o f a q u i n o id
s t r u c t u r e ( 4 3 ) .
N ie m a n n 's h y p o t h e s i s was a c c e p t e d w ith o u t q u e s t i o n
(fo r a d e c a d e u n t i l some new f i n d i n g s i n t h i s l a b o r a t o r y
}
I
[ re v e a le d t h e i m p o r t a n t r o l e o f t h e s i d e c h a i n . One
i
s i g n i f i c a n t d i s c o v e r y I n t h i s l a b o r a t o r y i s t h a t i f t h e
a l a n y l s i d e c h a i n o f t h y r o x i n e i s r e p l a c e d b y a p r o p i o n i c
a c i d c h a i n , th e r e s u l t i n g compound ( I V ) , t h y r o p r o p i o n i c
^ ^ - C H 2 CH2 C00H H J - ° \ ^ “ 0H2 CH2 C00H
IV V
a c i d , shows t h e h i g h e s t a c t i v i t y ( c a . 130 tim e s t h a t o f D,
L - th y r o x i n e ) y e t fo u n d f o r t a d p o l e m e ta m o rp h o sis ( 1 2 , 13)
an d a n o th e r r e p o r t e d f i n d i n g I s t h a t t h e m e ta - is o m e r (V) o f
t h y r o p r o p i o n i c a c i d p o s s e s s e s a b o u t 2 % t h y r o x i n e a c t i v i t y
i n s t e a d o f i n a c t i v i t y ( 1 3 ) . T hese f i n d i n g s s u g g e s t t h a t th e
q u i n p id s t r u c t u r e may n o t be t h e o n ly r e q u ir e m e n t f o r
p h y s i o l o g i c a l a c t i v i t y .
j An e x c e e d i n g ly im p o r ta n t d i s c o v e r y , made e a r l i e r I n
t h i s l a b o r a t o r y , i s t h a t t h e h a lo g e n s u b s t i t u e n t s on t h e
prim e r i n g o f t h y r o x i n e a r e n o t e s s e n t i a l f o r t h y r o x i n e
a c t i v i t y ; I n d e e d , i f th e two i o d i n e atom s i n t h e 3 ' , 5 ' -
p o s i t i o n s a r e r e p l a c e d by two m e th y l g r o u p s , t h e r e s u l t i n g
5
compound (V I)
HO i-0 ~ < '-CHpCHCOOH
NH
VI
has h i g h e r a c t i v i t y t h a n t h y r o x in e i t s e l f ( 1 2 ) . T h is i s i n
d i r e c t o p p o s i t i o n t o t h e v ie w s o f L ipm ann ( 3 8 ) , who
s u g g e s t e d t h a t e l e c t r o n - a t t r a c t i n g s u b s t i t u e n t s ( a s h a lo g e n
o r n i t r o ) , i n t h e s e p o s i t i o n s , a r e r e q u i r e d t o p ro m o te
jth y ro x in e a c t i v i t y i n a n a lo g s o f t h y r o x i n e .
3 . P u r p o s e s o f t h i s i n v e s t i g a t i o n . — I t was th e
p u rp o s e o f t h i s w ork to c a r r y o u t e x p l o r a t o r y s t u d i e s i n th e
f o llo w in g d i r e c t i o n s j
a) To i n i t i a t e w ork to w a rd th e s y n t h e s i s o f
jth y ro x in e a n a lo g s w i t h b u lk y s u b s t i t u e n t s i n t h e
3 1 , 5 ' - p o s i t i o n s •
B ecau se o f t h e s u r p r i s i n g r e s u l t s i n t h e t e s t i n g o f
jcompound V I , o t h e r 3 ' , 5 f a l k y l - s u b s t i t u t e d t h y r o n i n e s a r e o f
im m e d ia te i n t e r e s t . I t was s u g g e s te d b y P r o f e s s o r K h a ra s c h
t h a t th e u s e o f b u lk y s u b s t i t u e n t s , e . g . i s o p r o p y l a n d /o r
t - b u t y l c o u ld be o f s p e c i a l I n t e r e s t , s i n c e th e y (1 ) w ould
p r e s e n t an i n t e r e s t i n g p ro b le m i n s y n t h e s i s ; ( i i ) w ould be
o f v a lu e f o r t e s t i n g f o r th y r o x in e a c t i v i t y , an d e s p e c i a l l y
6
as c o m p e ti t iv e i n h i b i t o r s o f t h y r o x i n e , i f th e s t e r i c
e f f e c t s o f t h e l a r g e g ro u p s b lo c k e d t h e a c t i o n o f t h e
horm one; an d ( i i i ) w ould h av e v a lu e i n c l a r i f y i n g th e
i
r e l a t i o n o f s t r u c t u r e a n d a c t i v i t y o f t h y r o x i n e a n a l o g s .
| I t was r e c o g n i z e d t h a t t h i s f i e l d o f w ork w ould be a
i
jvery e x t e n s i v e one* N e v e r t h e l e s s , i t was d e s i r e d t o
e s t a b l i s h w h e th e r o r n o t s u c h s y n t h e s e s w ere f e a s i b l e .
b) To f i n d w h e th e r a t h i o p h e n o l , i n p l a c e o f a
p h e n o l, c o u ld be u s e d i n d e v e lo p in g a new s y n t h e s i s o f t h e
js u lf u r a n a lo g o f t h y r o x i n e , s i m i l a r t o th e m eth o d d e v e lo p e d
o j t h e G laxo w o rk e rs f o r t h y r o x i n e i t s e l f ( t h e m eth o d
jdeveloped i n G laxo L a b o r a t o r y , E n g la n d , w i l l be d i s c u s s e d i n
C h a p te r I I o f t h i s t h e s i s ) .
The r o l e o f t h e d ip h e n y l e t h e r l in k a g e i n t h y r o x i n e
a c t i v i t y was i n v e s t i g a t e d by H a r in g to n ( 1 9 4 8 ) , who r e p l a c e d
the o x ygen atom i n t h e e t h e r l i n k a g e by s u l f u r . The
r e s u l t i n g compound (V II)
1 ) = \
- S - Q - C H 2 CHC0 0 H
I NHg
V I I
was fo u n d t o show 20$ t h y r o x in e a c t i v i t y ( 2 5 ) , b u t o n ly one
p r e l i m i n a r y t e s t i n g r e s u l t was e v e r r e p o r t e d . I t was
c o n s i d e r e d t h a t t h i s s u l f u r a n a lo g o f t h y r o x i n e c o u ld ,
I
h o w e v e r, be s y n t h e s i z e d by a b e t t e r m eth o d t h a n t h a t w h ich
|
H a r in g to n a p p l i e d . One o b j e c t i v e o f th e p r e s e n t w o rk ,
t h e r e f o r e , was t o e x p lo r e th e r o u t e t o t h e s u l f u r a n a lo g s o f
b o th t h y r o x i n e an d t h y r o p r o p i o n i c a c i d by a m ore d i r e c t
m e th o d . The t h y r o x i n e a c t i v i t y o f t h e s u l f u r a n a lo g o f
I
jth y r o p r o p io n ic a c i d w i l l c e r t a i n l y be o f s p e c i a l i n t e r e s t
( Lnd s i n c e t e s t i n g o f t h e H a r in g to n p r e p a r a t i o n was e n t i r e l y
i n a d e q u a t e , i t i s p la n n e d t o su b m it c e r t a i n o f t h e s e
compounds f o r t e s t i n g . -
c) D u rin g t h e c o u rs e o f t h i s w o rk , a new s y n t h e s i s
o f t h y r o x in e was b r i e f l y r e p o r t e d by H illm a n ( 3 4 ) . T h is
in v o lv e d t h e r e a c t i o n o f b is - p -m e th o x y p h e n y lio d o n iu m s a l t s
( V I I I ) ( 6 ) f o r th e d i r e c t a r y l a t i o n o f
[CH3 0 - ^ / “ I “\ )-0C H 3 ]* ( H a lid e ) '
V I I I
d i i o d o t y r o s i n e ( i n t h e fo rm o f i t s N - a c e t y l e t h y l e s t e r ) .
iThis ty p e o f r e a c t i o n i s a n a p p l i c a t i o n o f B e r i n g e r 's w ork
jon p h e n y l a t i o n w ith io d o n iu m s a l t s ( 6 ) . S in c e H i l l m a n 's
work was r e p o r t e d o n ly a s a b r i e f c o m m u n ic a tio n , a n d i n view;
■ |
o f i t s p o s s i b l e s i g n i f i c a n c e t o t h e s y n t h e t i c p ro g ra m i n our
own w o rk , i t was d e s i r e d t o t r y t o e x p lo r e t h e c o n d i t i o n s
n e c e s s a r y f o r t h i s s y n t h e s i s .
CHAPTER I I
THE "GLAXO-MODIFICATION" OP THE
UXLMANN-NADAI REACTION
I t i s w e l l known t h a t a r o m a tic h a lo g e n compounds i n
w hich t h e h a lo g e n i s a c t i v a t e d hy n i t r o g ro u p s i n th e
D rth o - a n d p a r a - p o s i t i o n s w i l l r e a d i l y u n d e rg o e t h e r
f o r m a tio n w ith e i t h e r a l c o h o l s o r p h e n o l s .
NOg
V
Ar-OH 4 X -^ R --------* ■ A r O -^ /p-R X = H a lo g e n
/
NOg
l a r i n g t o n (26) a p p l i e d t h i s p r i n c i p l e to th e s y n t h e s i s o f
th y r o x in e a n d t h e G laxo w o rk e rs ( 8 ) v e r i f i e d i t s
s u i t a b i l i t y . As p h e n o ls a r e m ore r e a d i l y a v a i l a b l e t h a n th e
c o r r e s p o n d in g h a lo g e n o -c o m p o u n d s , i t was deem ed n e c e s s a r y
t h a t s u c h p h e n o l i c d e r i v a t i v e s s h o u ld be em p lo y ed a s
s t a r t i n g m a t e r i a l s f o r a n y s im p le t h y r o x i n e s y n t h e s i s . The
G laxo w o rk e rs a p p l i e d B a d d i l e y ’s m eth o d (2) a s f o l l o w s .
NOg
-R ■ » POCI3
CgHg-NfGgHgJg
NOg
NOg
C l -
R = CHO, CH3 , CHgCHgC00CgH5
9
Somewhat l a t e r , a t t e n t i o n was draw n t o th e T Jllm ann-N adai
r e a c t i o n , w h ich was e l u c i d a t e d by B o rsc h e (7) a s f o l l o w s .
Ar-OH « CH3 -<( V S 0 2C1 A r -0 - S 0 2* \ > C H 3
p y r i d i n e
[A r- ] * [S03 - 4 V oh3 1
HC1
A r-C l CH3 -K >>-S03H + p y r i d i n e
Ar = -K )>-R R — N02
3y f o l l o w i n g t h i s p r o c e d u r e , th e G laxo w o rk e rs f a i l e d to
o b t a i n th e c h lo ro -c o m p o u n d s fro m Ar-OH (R = CHO, CH3 ,
CH2 CH2 GG0 C2 H5 ) , b u t r e s u l t s s u g g e s t e d a n ew * ap p ro ach t o
th e s y n t h e s i s o f t h y r o x i n e . Prom B o r s c h e fs i n t e r p r e t a t i o n
( a b o v e ) , t h e y th o u g h t t h a t r e p l a c e m e n t o f th e m i n e r a l a c i d
(HCl) by p h e n o l m ig h t r e s u l t i n th e f o r m a t io n o f a d ip h e n y l
e t h e r . T h is s p e c u l a t i o n was c o n firm e d an d t h i s r e a c t i o n
p ro v ed f e a s i b l e i n many r e s p e c t s . The g e n e r a l s t e p s o f t h i s
m eth o d w ere f o r m u la te d a s f o l l o w s .
/
NOg
SOgCl * HO
NO
p y r i d i n e
c h 3 ^ - s o 2- o - ^ v r -------------------*
NOg
/ = \ /==\ r / = \ p-R»-G6H4-OH
f ( / - O - E r [ 0 H3 - O - s ° 3 ] ‘ — : — '
NOg
R = CH3> CHgCHgCOOCgHgj R» = 0CH3
10
I n t h i s r e a c t i o n , p y r i d i n e was u s e d a s a s o l v e n t and
t h e i s o l a t i o n o f th e q u a t e r n a r y s a l t was u n n e c e s s a r y . T h is
r e a c t i o n h a s b e e n a p p l i e d s u c c e s s f u l l y i n t h i s l a b o r a t o r y
f o r th e s y n t h e s i s o f many new a n a lo g s o f t h y r o x i n e and I t s
u s e f o r th e s u l f u r a n a lo g s t h e r e f o r e seem ed l o g i c a l .
CHAPTER I I I
DISCUSSION OF EXPERIMENTAL WORK
j A. S t u d i e s Toward t h e S y n t h e s i s o f th e S u l f u r A n a lo g s
o f T h y ro x in e and D e s a m in o th y ro x in e
1* The S u l f u r A nalog o f D e s a m i n o t h y r o x i n e The
p r e c u r s o r s r e q u i r e d f o r t h e s y n t h e s i s o f t h e s u l f u r a n a lo g
j>f d e s a m in o th y r o x in e a r e p - m e th o x y th io p h e n o l a n d e t h y l
4 - h y d r o x y - 3 ,5 - d in i t r o h y d r o c i n n a m a te * The s y n t h e s i s p la n n e d
f o r t h i s a n a l o g , from t h e s e p r e c u r s o r s , i s shown i n F ig u r e
L.
The p r e c u r s o r , e t h y l 3 , 5 - d i n l t r o l
ly d r o x y h y d ro c in n a m a te , was p r e p a r e d from
p - h y d ro x y b e n z a ld e h y d e by f o l l o w i n g th e d i r e c t i o n s d e s c r i b e d
by K h a r a s c h , K a lf a y a n , a n d A r t e r b e r r y ( 3 6 ) . The s y n t h e t i c
s e q u e n c e f o r t h i s p r e p a r a t i o n i s shown below *
HO-
O
-CHO
r e a c t i o n
P e r k i n
CH0CH9COOH CH=CHCOOH
K0 2
H O -Q -C H gCH gG O O CgH g
CHgCHgCOOH
NOg
NOg
NOg
HO-^-CHgCHgCOOCgHg — —
NOo'
N0<
L> p y r i d in e
^ CHs-^-SOgO-r^-OHgeHgCO OCgHg -------------- —
N0 <
r
N 0 {
/
^GHgGHgCOOCgHg J + / " CH3 - Q - S 0 3 J ~
NOg
p-CH 3 0 -C 6H4 -SH
/
* ° 8
Fd-C
/
NHr
CKsO-V^-S-^-GHgOHgOOOGgHg CHsOHQ-S-Q-GHgGHgGOOCgHg
NOg
C ^O -Q -S -Q -C K g C H g C O O C g H s - 1 ^ 1 GH 3 0 - Q - S - ^ - C H 2 CHgG00H liH O -Q -S -Q -G H g C H g C O O H
I I I
2 1 2
NHg
1 . d l a z o t l a a t i o n
2 . Sandmeyer
r e a c t i o n
1 2
H O -{ ^-S-O -G H gG H gG O O H
I
HG“V / * “S“ n ^ " GH 2 GH 2 CGOH
I I
-Figure 1 . The p ro p o se d seq u en ce o f r e a c t i o n s f o r th e s y n t h e s i s o f th e s u l f u r a n a lo g
o f d e sa m in o th y ro x in e and i t s t r i i o d o analo g *
i The P e r k i n c o n d e n s a t io n p r o c e e d e d w e l l , p r o v i d e d
jfchat th e t e m p e r a tu r e o f t h e r e a c t i o n m ix tu r e was k e p t
s t e a d i l y a t 1 4 0 -1 4 5 °G. The r e a c t i o n m ix t u r e was
ja e te ro g e n e o u s a n d th e s o l i d t e n d e d t o a d h e re t o th e b o tto m
jof t h e f l a s k . The l a t t e r phenom enon l e d t o o v e r h e a t i n g an d
. . . . . . .. . . ..
t o th e f o r m a t io n o f a n i n s o l u b l e s c a l e w h ic h was v e r y h a r d
j . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ' ' . . . . . . . . . . . . . . . . . . . . . . •
jto ta k e o u t* To a v o id t h i s t r o u b l e , a c o n s t a n t t e m p e r a tu r e
r e a c t i o n v e s s e l was u s e d a n d th e r e a c t i o n p ro c e e d e d
S m o o th ly , i n h i g h y i e l d (78JS»). The p -h y d ro x y c in n a m ic a c i d
was n o t i s o l a t e d , b u t was c o n v e r t e d d i r e c t l y t o
p -h y d ro x y h y d r© c in n a m ic a c i d , b y n i c k e l - c a t a l y z e d
l y d r o g e n a t i o n . The s u b s e q u e n t n i t r a t i o n a n d e t h y l a t i o n w ere
s a r r i e d o u t by th e u s u a l p r o c e d u r e . S p e c i a l c a r e m u st be
t a k e n w ith t h i s d i n i t r o com pound, w h ic h may be e x p l o s i v e on
e v a p o r a t i o n o f i t s s o l u t i o n , an d w h ic h a l s o a t t a c k s s k i n
j e r i o u s l y .
The p - m e th o x y th io p h e n o l was p r e p a r e d a c c o r d in g to
t h e p r o c e d u r e d e s c r i b e d by S u t e r an d H an sen ( 5 3 ) • T h is
p r e p a r a t i o n in v o lv e d d i a z o t i z a t i o n o f p - a n l s i d i n e , f o llo w e d
t y r e a c t i o n w i t h p o ta s s iu m e t h y l x a n t h a t e , a n d th e
d e c o m p o s itio n o f th e l a t t e r t o t h e d e s i r e d t h i o p h e n o l by
a l k a l i .
h n o 2 k s c ( s ) o c 2 h 5
s
|0H3O-Q-liHg ch30 - Q - k2- '
o
I I
* GH3 0 - ^ J - N 2 -SC -0C 2H5
1 . KOH
v 2 . (H -)
CH3 0 - < r j- S H
Q
The a t t e m p t s t o s y n t h e s i z e p - m e th o x y th io p h e n o l by a
new r o u t e , w h ic h h a d b e e n s u c c e s s f u l f o r th e s y n t h e s i s o f
s i m i l a r t h i o p h e n o l s by K h a ra s c h an d S w id le r ( 3 5 ) , w ere n o t
s u c c e s s f u l ( c f . a l s o p . 2 0 )*
The c o u p lin g o f e t h y l 3 , 5 - d i n i t r o - 4 -
h y d ro x y h y d ro c in n a m a te a n d p - m e th o x y th io p h e n o l was a c h ie v e d
by u s i n g th e G laxo m o d i f i c a t i o n o f t h e U llm a n n -N a d a i
r e a c t i o n ( s e e C h a p te r I I ) . As th e e x p e r i m e n t a l r e s u l t s have
show n, th e f o r m a t io n o f t h e s u l f i d e l i n k a g e o c c u r s sm o o th ly
a n d t h e y i e l d (96%) i s much h i g h e r t h a n i s th e y i e l d , 6 5 $ ,
be th e f i r s t exam ple o f th e u s e o f a t h io p h e n o l I n t h i s
a p p ro a c h t o th e s y n t h e s i s o f a s u l f u r a n a lo g o f t h y r o x i n e .
The h y d r o g e n a t i o n o f e t h y l 4 -p -m e th o x y th io p h e n o x y -
euuyx ^ t-p -x u e c h o x y th lo p h e n o x y -3 ,5 -d ia m in o h y d ro c ln n a m a te • T he|
i n th e s y n t h e s i s o f t h e e t h e r l i n k a g e ( 1 7 ) . T h is a p p e a rs tc
|3 ,5 - d i n l t r o h y d r o e i n n a m a t e p r o c e e d e d s m o o th ly , u s i n g
p a ll a d i u m on c h a r c o a l a n d h y d r o g e n , a t 45 p . s . i . , t o g iv e
l a t t e r ' w a s n o t a c t u a l l y I s o l a t e d , b u t was c o n v e r te d
d i r e c t l y , by d i a z o t i z a t i o n a n d s u b s e q u e n t Sandm eyer
1 5
r e a c t i o n , t o y i e l d e t h y l 4 - p - m e th o x y th io p h e n o x y - 3 ,5 -
i ii o d o h y d r o c i n n a m a t e .
| On t r e a t m e n t o f e t h y l 4 - p - m e th o x y th io p h e n o x y - 3 ,5 -
d iio d o h y d r o c in n a m a te w i t h a m ix tu r e o f a c e t i c a c i d a n d
i i
h y d r o c h l o r i c a e i d , a q u a n t i t a t i v e c o n v e r s i o n t o a compound \
| " ’ ■ ■ ■ ■ ■ ...................
R e li e v e d t o be t h e a c i d , 4 - p - m e th o x y th io p h e n o x y - 3 ,5 - !
jd iio d o h y d ro c in n a m ic a c i d , was a c h ie v e d *
I t i s o f i n t e r e s t t o n o te t h a t t r e a t m e n t o f e t h y l
1- p - m e th o x y th io p h e n o x y - 3 ,5 - d iio d o h y d r o c in n a m a te w i t h a
m ix t u r e o f a c e t i c a n d h y d r i o d i c a c i d s , i n th e a t t e m p t t o
c le a v e b o th th e e s t e r a n d e t h e r l i n k a g e s , gave a p r o d u c t
whose a n a l y s i s f o r i o d i n e c o r r e s p o n d s v e r y w e l l f o r th e
t r i i o d o d e r i v a t i v e show n b e lo w .
C H 3 O - 0 > - S - ^ - C H 2 GH2COOC2H5 H 0 -^ -S -< Q -C H 2 C H 2 C00H
I I
I t i s b e l i e v e d , b u t n o t y e t p r o v e d , t h a t t h e e x p l a n a t i o n f o r
t h i s o b s e r v a t i o n i s t h a t d e c o m p o s itio n o f t h e h y d r i o d i c a c id
l i b e r a t e s i o d i n e (w h ic h c an a lw a y s be o b s e r v e d i n t h e s e
i
r e a c t i o n s ) an d t h a t i o d i n a t i o n o f t h e p rim e r i n g t h e n o c c u rs
by a c t i o n o f t h i s l i b e r a t e d i o d i n e . T h is b e h a v i o r i s n o t
■
{found w ith th e oxygen a n a l o g , e t h y l 4 - p - m e th o x y p h e n o x y -3 ,5 -
d i io d o h y d r o c in n a m a t e . I n th e l a t t e r c a s e , t o o b t a i n t h e
t r i - a n d t e t r a - i o d i n a t e d com pounds, s e p a r a t e a n d c o n t r o l l e d
1 6
i o d i n e t i o n s a r e r e q u i r e d . T h is p o s s i b l e s y n t h e s i s o f th e
t r i i o d o "1 d e r i v a t i v e o f th e s u l f u r a n a lo g o f t h y r o x i n e i s o f
j i n t e r e s t b e c a u s e th e t r i i o d o a n a lo g o f t h y r o x i n e i t s e l f h a s
[such r e m a r k a b le p h y s i o l o g i c a l a c t i v i t y .
* The c o n v e r s i o n o f 4 - p - m e th o x y th io p h e n o x y - 3 ,5 -
d iio d o h y d r o c in n a m ic a c i d t o 4 - ( 4 *- h y d r o x y - 3 * , 5 '-
5
jd iio d o th io p h e n o x y ) - 3 , 5 - d iio d o h y d r o c in n a m ic a c i d a n d th e f u l l
p r o o f o f s t r u c t u r e f o r 4 - ( 4 '- h y d r o x y - 3 f- i o d o t h i o p h e n o x y ) -
3 , 5 - d iio d o h y d r o c in n a m ic a c i d s t i l l a w a i t f u r t h e r w o rk .
2 . R e s u l t s to w a rd t h e s y n t h e s i s o f th e s u l f u r
a n a lo g o f t h y r o x i n e . — I n 1 9 4 8 , H a r in g to n (2 5 ) s y n t h e s i z e d
th e s u l f u r a n a lo g o f t h y r o x in e fro m p - m e th o x y th io p h e n o l and
3 , 4 , 5 - t r i l o d o h i t r o b e n z e n e by a n e l a b o r a t e p r o c e s s i n v o l v i n g
fche t e n s t e p s show n b e lo w .
CH3 -<0 -S H ♦ I - Q - S O g — * CH3 0 - Q - S - ^ } - I I O 2
I I
— RKHg — ► R N gC l — ► R O N > RCHO — * - RGHgOH —-v R CH gCl
GH3 G" 0 " S~0 " GH2 G1 * * CH3 C0 RHCH(C0 0 CgH5 ) g -------------
I
I
I
eH3 0 - ^ - S - ^ - G H g C ( G 0 0 CgH5 ) g ------CH3 0 -{ ^ )-S -{ ^ -C H g C H C O O H
I NHC0 CH3 I KHg
> - H O - ^ - S - ^ - C H g ^ J H C O O H R = CH3 0 - { ^ - S - X ’
KHg I
17
The p r e s e n t p u r p o s e was t o i n v e s t i g a t e w h e th e r th e
'J llm a n n -N a d a i r e a c t i o n c a n be a p p l i e d t o t h i s s y n t h e s i s .
Jn d e r m o d if ie d c o n d i t i o n s , i t was fo u n d t h a t i t c o u ld be
a p p l i e d . T h is r e a c t i o n , w h ich i s s i m p l e r a n d m ore
c o n v e n i e n t t h a n t h e H a r in g t o n p r o c e s s , s h o u ld be o f
! - ' ■ '
c o n s i d e r a b l e v a lu e t o t h e s y n t h e s i s o f th e s u l f u r a n a l o g .
The s y n t h e t i c se q u e n c e i s a s f o l l o w s .
HO
HO- CHoCHCOOH >-CHoCHCOOH
HE
NO
HO NH
NHCOCH
NO
HO
v
ch3 o- ^-CHgCHCOOCgHg
n h co ch3
The p r e c u r s o r , e t h y l L - 3 ,5 - d i n i t r o - W -
a c e t y l t y r o s i n a t e , was p r e p a r e d fro m L - t y r o s i n e by f o l l o w i n g
t h e p r o c e d u r e d e s c r i b e d by C h a lm e rs , D ic k s o n , E l k s , an d Hems
(1 4 )« The p - m e th o x y th io p h e n o l was p r e p a r e d from p -
a n i s i d i n e , a s a l r e a d y d i s c u s s e d b e f o r e ( s e e p . 1 3 ) . The
c o u p li n g o f e t h y l L - 3 , 5 - d i n i t r o - N - a c e t y l t y r o s i n a t e a n d
p - m e th o x y th io p h e n o l was a c h ie v e d by a p p ly i n g t h e G la x o -
m o d i f i c a t i o n o f t h e X Jllm ann-N adai r e a c t i o n .
F u r t h e r s t e p s to w a rd t h e s y n t h e s i s o f
L - ,,t h i o t h y r o x i n e H ( L - 3 , 5 - d i l o d o - 4 - ( 4 ’- h y d r o x y - 3 ’ , 5 ’-
d i i o d o t h i o p h e n o x y ) - p h e n y l a l a n i n e ] a r e p r o p o s e d a s shown i n
F ig u r e 2 .
3* The r e s u l t s o f a t t e m p t s t o e f f e c t a new
s y n t h e s i s o f p - m e th o x y th io p h e n o l. — I n 1 9 5 4 , K h a ra s c h a n d
S w id le r r e p o r t e d a new s y n t h e s i s o f some t h i o p h e n o l s , i . e .
p - t h i o c r e s o l , p - x e n y l t h i o l , p - c h l o r o t h i o p h e n o l ,
p - b r o m o th io p h e n o l, a n d t h i o p h e n o l ( 3 5 ) . The new m eth o d
i n v o lv e d th e s y n t h e s i s o f th e r e q u i r e d a r y l 2 , 4 -
d l n i t r o p h e n y l - s u l f i d e s , f o llo w e d by a l k a l i n e c le a v a g e o f the
l a t t e r t o y i e l d th e t h i o p h e n o x i d e , w h ic h on a c i d i f i c a t i o n
gave th e t h i o p h e n o l .
ArH / ! ^'N°2 CH,OH-KOH ,NOg
0aN- O " SC1 JiOiJ °2N- 0 - SAr g4 ' ArSH * 02N-Q-00H3
m 2
ch 3 o -4
*N0 o
^-CHgCHGOOGgHg
NHCOCH,
GH3 0
W z
•S' VcH2G H C 00C g H 5
2 j J
MHg NHCOCH5
OH 3 o / ~ A - S - ^ ~ ^ - O H 2 CHGOOe2H5 -> HG-
KHCOGH,
I I
H O - / \-S> -
I
CHqCHCOOH
I
V
-CHgCHCOOH
NHg
HO *
Y
I
)-CHgCHCOOH
NHg
F ig u re 2 . The p ro p o se d f u r t h e r s t e p s f o r th e s y n t h e s i s o f th e s u l f u r
a n a lo g o f th y r o x in e .
20
I n th e p r e s e n t w ork I t was d e s i r e d t o e x te n d t h i s m eth o d t o
t h e s y n t h e s i s o f t h e a n a lo g o u s com pound,
■ p -m e th o x y th io p h e n o l, w h ic h was th e d e s i r e d p r e c u r s o r f o r th e
i
I
|s y n t h e s i s o f t h e s u l f u r a n a lo g s o f t h y r o x i n e . The p la n n e d
s y n t h e t i c se q u e n c e i s shown h e lo w .
The r e q u i r e d p r e c u r s o r , 2 , 4 - d i n i t r o p h e n y l p -m eth o x y p h e n y 1
s u l f i d e , was s y n t h e s i z e d , on a p r e p a r a t i v e s c a l e , by th e
m ethod o f M cQ u arrie ( 4 0 ) . H ow ever, on a tt e m p t e d a l k a l i n e
c l e a v a g e , th e d e s i r e d t h i o p h e n o l was n o t f o u n d . S e v e r a l
a tte m p ts w ere m ad e, b u t o n ly 2 , 4 - d i n i t r o a n l s o l e and
2 , 4 - d i n i t r o p h e n o l w ere, i s o l a t e d . None o f t h e d e s i r e d
t h io p h e n o l was o b t a i n e d , a lt h o u g h i n d i c a t i o n s o f i t (b y o d o r
on a c i d i f i c a t i o n o f th e a l k a l i n e c le a v a g e m ix tu r e ) w ere
o b s e r v e d . T h is may be due t o t h e f a c t t h a t
p - m e th o x y th io p h e n o l i s so u n s t a b l e i n t h e p r e s e n c e o f t h e
d i n i t r o compound t h a t f u r t h e r r e a c t i o n s o c c u r .
gh3 o 4 OgN-
NOg
V sci
NOg
VNOg
NaOCHg
3 ( I s o l a t i o n
u n s u c c e s s f u l )
(Found)
21
B. S t u d i e s Toward t h e S y n t h e s i s o f T h y ro x in e A n a lo g s w ith
B ulky G roups i n th e S 1,® 1- P o s i t i o n s o f t h e P rim e R ing
The compound planned to he sy n th e s iz e d in t h is work
was e t h y l 3 ,5 - d i n i t r o - 4 - ( 3 * , 5 ' - d iis o p r o p y l- 4 '-
jhydroxyphenoxy)-hydrocinnam ate. The p recu rso rs o f t h is
J j
.compound a r e e t h y l 3 ,5 » d i n i t r o - 4 - h y d r o x y h y d r o c i n n a m a te an d
3 ,5 - d i i s o p r o p y l h y d r o q u i n o n e • The s u c c e s s o f t h i s c o u p lin g
r e a c t i o n was p la n n e d to d e p en d on th e p r e d i c t i o n t h a t t h e
i s o p r o p y l g ro u p s w o u ld p r o v id e s u f f i c i e n t s t e r i c h in d r a n c e
so t h a t t h e 1 - h y d r o x y l r a t h e r t h a n t h e 4 - h y d r o x y l w ould
r e a c t i n t h e c o u p lin g r e a c t i o n w i t h t h e e t h y l 3 , 5 - d i n i t r o -
i- h y d r o x y h y d r o c in n a m a te . The p r e p a r a t i o n o f e t h y l 3 , 5 -
d i n itr o - 4 - h y d r o x y h y d r o c in n a m a te h a s b e e n d i s c u s s e d b e f o r e
( c f . p . 1 1 ) . To s y n t h e s i z e t h e r e q u i r e d i
d l is o p r o p y lh y d r o q u i n o n e , t h e f o l lo w in g m eth o d s w ere t r i e d .
i ) I n a n a lo g o u s w ork o f e a r l i e r i n v e s t i g a t o r s , th e
a i s u b s t i t u t e d h y d ro q u in o n e was u s u a l l y s y n t h e s i z e d by th e
E lb s p e r s u l f a t e m eth o d
R R
T h is m eth o d was t r i e d f i r s t b u t t h i s a t t e m p t was n o t
s u c c e s s f u l , b e c a u s e i n th e c a s e o f d i i s o p r o p y l p h e n o l , t h e
s t e r i c a l l y h i n d e r e d h y d r o x y l ( o f t h e M c r y p t o p h e n o l s w) f a i l s
22
t o form t h e sodium s a l t a n d , t h e r e f o r e , th e
f liis o p r o p y lp h e n o l i s n o t s o l u b l e i n a l k a l i n e s o l u t i o n , w h ich
•is th e i m p o r t a n t c o n d i t i o n i n t h e E lb s p e r s u l f a t e o x i d a t i o n *
T h u s, i n t h e p r e s e n t s t u d y , i t was fo u n d t h a t th e E l b ' s
jn eth o d c o u ld n o t be a p p l i e d s u c c e s s f u l l y i n t h i s
j
p r e p a r a t i o n *
i i ) I n 1 9 5 2 , B r u i c e , K h a r a s c h , a n d W ln z le r
s y n t h e s i z e d th e d im e th y l h y d ro q u in o n e v i a th e f o l l o w i n g
s e q u e n c e , w i t h h i g h e r y i e l d t h a n was o b t a i n e d i n t h e E lb s
i
o x i d a t i o n o f t h e 2 , 6 - x y l e n o l .
R R R R
- R R
T h is m eth o d was t r i e d f o r th e d i - i s o p r o p y l a n a l o g ,
b u t d i d n o t s u c c e e d . The b r o m in a ti o n o f th e p h e n o l r e s u l t e d
In a n o ra n g e compound i n s t e a d o f t h e b r o m o - s u b s t i t u t e d
p h e n o l, w h ich was e x p e c te d t o be c o l o r l e s s . The o ra n g e
sompound was p re su m e d t o be a s u b s t i t u t e d d lp h e n o q u in o n e a s
3hown b e lo w (R = i s o p r o p y l ) , b u t was n o t f u r t h e r
I n v e s t i g a t e d .
l i i ) F i n a l l y , a new way was i n v e s t i g a t e d a n d th e
I
d i s u b s t i t u t e d h y d ro q u in o n e was s y n t h e s i z e d s u c c e s s f u l l y by
jfo llo w in g th e se q u e n c e shown b e lo w (R - i s o p r o p y l ) #
R
\
R
HO>Y H C Mv ) ~ m 2
R
R = CH(CH3 ) 2
Ip o n t r e a t m e n t w i t h n i t r o u s a c i d a t 0 ° C ., th e
d i i s o p r o p y l p h e n o l , a y e ll o w o i l , was c o n v e r t e d t o a y e llo w
c r y s t a l l i n e com pound, 2 , S - d i i s o p r o p y l - 4 - n i t r o s o p h e n o l , i n
94% y i e l d # At low t e m p e r a t u r e ( - 2 0 ° G . ) , th e i s o m e r i c
com pound, 3 ,5 - d i i s o p r o p y l q u i n o n e o x im e , a c h o c o l a t e - l i k e
s o l i d , was fo rm e d . The oxime c o u ld be c o n v e r te d t o t h e
y e llo w n i t r o s o compound on r e c r y s t a l l i z a t i o n o r on h e a t i n g
w ith a c i d . The n i t r o s o p h e n o l was r e d u c e d e a s i l y by Raney
■ n ic k e l- c a ta ly z e d h y d r o g e n a t io n a t 25 p . s . i . an d room
t e m p e r a t u r e . The 2 ,6 - d i i s o p r o p y l - 4 - a m i n o p h e n o l was v e r y
u n s t a b l e a n d was c o n v e r t e d d i r e c t l y t o t h e
24
2 ,6 - d l i s d p r o p y l q u i n o n e by o x i d a t i o n w i t h f e r r i c c h l o r i d e .
The 2 , 6 - d i i s o p r o p y l q u i n o n e was n o t i s o l a t e d b u t was
V
c o n v e r te d t o t h e 2 ,6 - d i i s o p r o p y l h y d r o q u i n o n e by t h e
r e d u c t i o n w ith sodium h y d r o s u l f i t e (NagSgO^.).
The s y n t h e s i s o f e t h y l 3 , 5 - d i n i t r o - 4 - ( 3 ’ ,5 * -
i -
j d ii s o p r o p y l - 4 ’-h y d ro x y p h e n o x y ) -h y d r o c in n a m a te was a c h i e v e d
i .. ■ • '
i n t h e c o u p li n g o f e t h y l 3 ,§ - d i n it r o - 4 - h y d r o x y h y d r o e i n n a m a te
and 3 ,5 - d i i s o p r o p y l h y d r o q u i n o n e by t h e G lax o m o d i f i c a t i o n o f
lllm a n n - N a d a i r e a c t i o n (R * i s o p r o p y l )
R
\___
H 0”l } ~ 0E + H 0A ^-CHgCHgCOOCgHg
R
. R
p y r i d i n e
H O -^ ^-GHgCHgGOGCgHg
T sC l
F u r t h e r s t e p s to w a rd th e s y n t h e s i s o f 3 , 5 - d i i o d o -
l - ( 3 ’ , 5 1- d i i s o p r o p y l - 4 ’- h y d ro x y p h e n o x y )- h y d r o c in n a m ic a c i d
were p r o p o s e d a s f o l l o w s (R = i s o p r o p y l ) .
25
R R
H(K > - 0 -^J.-rO H 2 CH2 COOC2 H5
NOg
(1)
NHg
NO,
VHO-^J-O-^J-CHgCHgCOOCgHs
A NHg
(4)
R
( 2 )
pHgO-^i-O-^J-CHgGHgCOOCgHs E 0 - £ ) - 0 - l ^-CHgCHgCOOCgHs
NOg
/
R
/
I
(3)
(5)
R
' R ?
H O - ^ - 0-^)-CHgGHgC OOH
(7)
R I
L
(JHsO-^J-O-^J-CHgCHgCOOGgHg iS? GHsO-^-O-^J-CHgCHgCOOGgHs
R NHg R I
Ha© p r o p o s e d s t e p s 1 a n d 2 w ere t r i e d t w i c e , u s i n g
c a t a l y z e d h y d r o g e n a t io n w i t h p a l l a d i z e d c h a r c o a l , and
s u b s e q u e n t d i a z o t i z a t i o n a n d Sandm eyer r e a c t i o n , b u t th e
a t t e m p t s w ere n o t7 s u c c e s s f u l . The r e a s o n s f o r t h e s e
d i f f i c u l t i e s a r e n o t a s y e t c l e a r , b u t i t seem s l i k e l y t h a t
t h e p r e s e n c e o f t h e f r e e h y d ro x y l i n t h e 4* p o s i t i o n o f
e t h y l 3 , 5 - d i n i t r o - 4 - ( 3 1, 5 1- d i i s o p r o p y l - 4 ’-h y d ro x y p h e n o x y )-
ay d r o c irmama t e may be r e s p o n s i b l e f o r th e d i f f i c u l t i e s . The
s te p 4 was t r i e d tw ic e by a tt e m p t e d m e t h y l a t i o n w i t h
d ia z o m e th a n e , b u t o n ly th e u n r e a c t e d o r i g i n a l compound was
i s o l a t e d . T h is s t e p may be a t t a i n a b l e by th e m e t h y l a t i o n
26
w ith dime t h y l s u l f a t e , p r o v i d e d t h a t t h e e t h e r l i n k a g e o f
t h i s m o le c u le i s n o t c le a v e d u n d e r t h e r e a c t i o n c o n d i t i o n s .
An a l t e r n a t e s u g g e s t i o n i s , t h a t i n p l a c e o f 2 , 6 -
jd iis o p r o p y lh y d r o q u in o n e , th e c o r r e s p o n d i n g 4 - m e th o x y - 3 ,5 -
I
|d iis o p r o p y lp h e n o l he u s e d i n t h e s y n t h e s i s o f e t h y l 3 , 5 -
i ■
j d i n i t r o - 4 - ( 3 1,5 1- d i i s o p r o p y l - 4 ’-m e th o x y p h e n o x y ) -
h y d r o c in n a m a te • T hen th e p r o p o s e d s t e p s 5 , 6 , a n d 7 may he
f o l lo w e d . H ow ever, th e s y n t h e s i s o f 4 - m e th o x y - 3 ,5 -
d i i s o p r o p y l p h e n o l may p r e s e n t some p r o b le m s . I n t h e
s y n t h e s i s o f t h e a n a lo g o u s com pound, 4 - m e th o x y - 3 ,5 -
d i t e r t - b u t y l p h e n o l , K h a ra s c h a n d Saha c o u ld n o t i s o l a t e th e
d e s i r e d compound i n s e v e r a l a t t e m p t s .
G. R e s u l t s o f A tte m p ts t o S y n t h e s i z e T h y ro x in e hy th e
M ethod o f H illm a n
S in c e - H a r in g to n f i r s t s y n t h e s i z e d t h y r o x in e i n 1 9 2 6 ,
s e v e r a l d i f f e r e n t m eth o d s o f s y n t h e s i s h a v e 'b e e n d e v e lo p e d .
Uew r o u t e s a r e , h o w e v e r, s t i l l u n d e r i n v e s t i g a t i o n .
R e c e n t l y , a m eth o d f o r t h e p r e p a r a t i o n o f d i a r y l io d o n i u m
s a l t s became a v a i l a b l e ( 6 ) . T hese d ia r y l io d o n i u m s a l t s w ere
fo und t o be s o r e a c t i v e t h a t th e y c o u ld be u s e d a s g e n e r a l
a r y l a t i n g a g e n t s , j u s t a s a l k y l b ro m id e s f i n d u s e a s g e n e r a l
a l k y l a t i n g a g e n t s ( 6 ) . H illm a n a p p l i e d t h i s r e a c t i o n an d
c a r r i e d o u t i n i t i a l e x p e r im e n ts w h ic h w ere r e p o r t e d t o
s y n t h e s i z e t h y r o x i n e by t h e f o l lo w in g r e a c t i o n s .
[ ch3 o-<
\
\
H0CH3] I 4 HO- -CHgCHCOOCgHg
nhgoch3
27
WaOCH,
CH3 0H
» ch3q
V
I
CHs O - Q - O - 0 -
I
•CHgGHCOOH
KHC0CH3
-CHgCHCOOH
NHCOCH-i
1 . i o d i n a t i o n
-------------------------------
2 . H I 4 HOAc
-G**(\ y-CHgCHCOOH
I NHg
I n th e p r e s e n t w o rk , th e p r e c u r s o r , b i s - p -
m e th o x y p h e n y lio d o n iu m i o d i d e , was p r e p a r e d fro m a n i s o l e a n d
p o ta s s iu m i o d a t e a c c o r d i n g t o B e r i n g e r ‘s d i r e c t i o n (6) an d
im p ro v em en t o f y i e l d (fro m 11$ t o 20%) was m ad e, by v a r y i n g
s o l v e n t c o n d i t i o n s f o r t h i s p r e p a r a t i o n . The m echanism o f
t h i s r e a c t i o n h a s n o t y e t b e e n e l u c i d a t e d c l e a r l y , b u t th e
p ro b a b le se q u e n c e o f r e a c t i o n s f o r t h e p r e p a r a t i o n o f
b is - p -m e th o x y p h e n y lio d o n iu m i o d i d e a r e shown below *
28
2CH3 0 - ^ ■ » 2 H 0 -I ^ ° : ------------ 2GH3 G - ^ - I ^ ° 4 2HgO
2CH3 0 - < Q - I ^ 4 2 ^ - 0 C H 3 - ^ 2CH3 0 - Q - I = 0 4 2 H 0 -< Q -0 C H 3
OH ,
2 GH3 0 - ^ - I * 0 -» 2 ^ - 0 CH3 ----- 2 GH3 0 - < ^ - I - < Q - 0 CH3
OH
I
2CH3 0 - { _ } - I - ^ - 0 C H 3 -r HgS04 , -------------- -—
[CH3 0 - Q - I - Q - 0 C H 3 } ^ S 0 4 — * 2HgO
[ C H s O - Q - I - Q - O G H s l ^ S O ^ - 4 2 1 "-------- —-------------- ^
2[CH3 0 - ^ - I - { ] ) - 0 C H 3 ] I 4 S04 ~
Wets 6CH3 0 - Q .4 2HI03 4 21" 4 HgS04 -------------------
2[CH3 O - Q » - I - 0 > - O C H 3 } I 4 2CH3 0 - ^ ) - 0 H 4 S04 " " 4 4HgO
A lth o u g h i t h a s n o t "been n o te d i n t h e l i t e r a t u r e t h a t
p -m e th o x y p h e n o l i s a p r o b a b le b y - p r o d u c t , a s u b s t a n c e ,
w hich was p re su m e d t o be th e p - m e th o x y p h e n o l, was i s o l a t e d
i n th e p r e s e n t w ork ( c f . e x p e r i m e n t a l ) .
i j - t y r o s i n e was i o d i n a t e d by th e p e r o x i d e m eth o d o f J u r d
;o th e p r o c e d u r e s d e s c r i b e d by B a rn e s a n d o t h e r s ( 4 ) .
The s y n t h e s i s o f 3 ,5 - d iio d o - 4 - p - m e th o x y p h e n o x y - N -
u c e t y l - L - p h e n y l a l a n i n e was c a r r i e d o u t a c c o r d i n g t o
H illm a n fs d i r e c t i o n a n d a c o l o r l e s s p r o d u c t ( t h e io d o n iu m
i o d i d e was y e llo w ) was i s o l a t e d . The c ru d e p r o d u c t m e l t e d
a t 1 9 0 -1 9 5 ° C . A c o l o r ch an g e ( c o l o r l e s s — 3 - y e llo w s-
a r a n g e —^ m e l t i n g ) was o b s e r v e d d u r in g th e 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 . The r e p o r t e d m e l t i n g p o i n t o f t h i s compound
A n o th e r p r e c u r s o r , e t h y l L - 3 ,5 - d i i o d o - N -
a c e t y l t y r o s i n a t e , was p r e p a r e d fro m L - t y r o s i n e i n t h e
■ follow ing s e q u e n c e .
I
HO-
<
CHgCHCOOH -CHgGHCOOH
NHg I NHg
I I
H 0- CHgCHCOOH
NHG0CH3
( y
CHgCHCOOCgHg
NHCOGH3 I I
(3 1 ) • The L - 3 , 5 - d i i o d o t y r o s i n e o b t a i n e d was a c e t y l a t e d w ith
a c e t i c a n h y d r id e a n d was s u b s e q u e n t ly e s t e r i f i e d a c c o r d i n g
30
was 1 9 6 -1 9 7 °C . ( 1 4 ) . The o b t a i n e d c ru d e p r o d u c t was
c r e a t e d w i t h a m ix tu r e o f h y d r i o d i c an d a c e t i c a c i d s a n d a
y e l l o w i s h p r o d u c t was o b t a i n e d . T h is p r o d u c t was p resu m ed
t o be 3 , 5 - d i i o d o - L - t h y r o n i n e and i t s t a r t e d m e l t i n g a t
2 1 Q °C ., w ith d e c o m p o s itio n , w i t h i n one m i n u t e . The m e l t i n g
i n t e r v a l was s h o r t e n e d when th e t e m p e r a t u r e was r a i s e d . I f
p la c e d on t h e b l o c k a t a b o u t 2 7 0 ° G ., i t m e l t e d im m e d ia te ly ,
rh e r e p o r t e d m e l t i n g p o i n t o f t h i s compound was 255°G . w i t h
d e c o m p o s itio n ( 1 4 ) . The m e l t i n g p o i n t d a t a o f t h e s e two
I ' ■ ■ : ....................
p r o d u c t s a r e c l o s e t o th e r e p o r t e d v a l u e s . F o r t h e p r e s e n t
p u r p o s e , a lt h o u g h t h e e le m e n ta r y a n a l y s e s w ere n o t c a r r i e d
3Ut, i t was r e c o g n i z e d t h a t H i l l m a n ^ a p p ro a c h t o t h i s
s y n t h e s i s seem ed t o be f e a s i b l e .
CHAPTER IV
I EXPERIMENTAL |
: - *
■ 1 . p -H y d ro x y h y d ro c ln n a m ic A c i d *— |
p -H y d ro x y b e n z a ld e h y d e (40 g . ) and 64 g . o f f r e 3 h l y f u s e d an d
| \ ’ • ■ ■ ■ ■
g ro u n d sodium a c e t a t e w ere w e l l m ix e d a n d p l a c e d i n a
p n e - l i t e r c o n s t a n t te m p e r a t u r e f l a s k f i t t e d w i t h a v i g r e u x
1
colum n h a v in g a d r y i n g tu b e on th e to p a n d a w a t e r - c o o l e d
c o n d e n s e r . The o u t s i d e cham ber o f t h i s f l a s k was h a l f
f i l l e d w ith a s o l v e n t whose b o i l i n g p o i n t i s a ro u n d
1 4 0 -1 4 5 °C . A c e t i c a n h y d rid e (100 m l . , r e d i s t i l l e d ) was i
Added a n d t h e m ix t u r e was r e f l u x e d f o r 24 h o u r s w ith
o c c a s i o n a l s t i r r i n g * I t was c o o le d t o 100°G . a n d p o u re d
i n t o one l i t e r o f 15$ so d iu m h y d r o x id e s o l u t i o n , w hich
c h a n g e d th e c o l o r fro m y e ll o w t o r e d . R aney n i c k e l a l l o y
(60 g . ) was a d d e d d u r in g a p e r i o d o f 3 t o 4 h o u r s , a t
6 0 - 7 5 ° C* H e a tin g was c o n t i n u e d on t h e ste a m b a t h f o r 2
h o u r s a f t e r a l l t h e Raney n i c k e l h a d b e e n a d d e d , c h a r c o a l
(5 g . ) was n e x t a d d e d a n d t h e warm s o l u t i o n was f i l t e r e d
th r o u g h a s i n t e r e d g l a s s f u n n e l . The r e s i d u e was w ashed
w ith two 50 m l. p o r t i o n s o f 2% sodium h y d r o x id e s o l u t i o n *
The f i l t r a t e was made a c i d t o Congo Red by u s i n g c o n c .
jh y d r o c h lo r ic a c i d a n d e x t r a c t e d w ith e t h e r . The e t h e r was
rem o v ed a n d t h e r e s u l t i n g v i s c o u s m ass was s u b lim e d a t 2 mm.
| 3 2
p r e s s u r e , i n a s u b l i m a t i o n p i s t o l - The w h ite s o l i d o b t a i n e d
was r e c r y s t a l l i z e d from a b e n z e n e - n - h e p ta n e s o l u t i o n a n d
c o l o r l e s s c r y s t a l s , m .p . 1 2 9 °C . (29*9 g . , 5 5 $ ) , w ere form ed*
i 2 . 3 ,5 - D f n itr o - 4 - h y d r o x y h y d r o c in n a m ic A c id *— I n a
| ■ ■ ............
500 m l. 3 -n e c k e d f l a s k , f i t t e d w ith s t i r r e r , th e r m o m e te r , j
;and d r o p p in g f u n n e r , p h l o r e t i c a c i d ( 2 7 .8 g . , 0 .1 7 m o le ) was
s ’ -
I d ls s o lv e d i n 220 m l. a c e t i c a n h y d r id e a n d c h i l l e d t o 2 c C.
j j i l t r i c a c i d (25 m l . , d s 1 .4 2 ) was a d d e d d ro p w ise d u r in g two
! ... . . .
h o u r s , k e e p in g t h e te m p e r a t u r e a t o r b e lo w 2 °C . The m ix tu r e
was s t i r r e d a n o t h e r 15 m in - a t - 5 ° C . a n d p o u r e d i n t o 500 g .
I c e . The s o l u t i o n was b o i l e d h a l f an h o u r a n d l e f t t o c o o l*
b e llo w c r y s t a l s ( 3 0 .2 g . ) w ere o b t a i n e d . The m o th e r l i q u o r
was e v a p o r a t e d t o s m a ll v o lu m e , y i e l d i n g 4 . 1 g . m o re , m .p .
i • •
135°G . ( 3 4 .3 g . , 8 0 $ ) .
3* E t h y l 3 ,5 - d i n i t r o - 4 - h y d r o x y h y d r o c l n n a m a t e . - - I n a
250 ® 1. f l a s k , f i t t e d w i t h a w a t e r - c o o l e d c o n d e n s e r , 1 4 .7 g*
(0 .0 5 7 m o le) o f 3 ,5 - d i n i t r o - 4 - h y d r o x y h y d r o c i n n a m i c a c i d was
d i s s o l v e d i n 120 m l. o f e t h a n o l ( a b s . ) and 10 m l. c o n c .
s u l f u r i c a c i d was a d d e d i n s m a ll p o r t i o n s . The m ix t u r e was
r e f l u x e d f o r two an d o n e - h a l f h o u r s , c o o l e d , an d w a te r was
added t o i t . The y e llo w c r y s t a l s o b t a i n e d w ere d i s s o l v e d in
c h lo r o f o r m a n d t h e s o l u t i o n was p a s s e d th r o u g h f i l t e r p a p e r
to rem ove t h e a d h e r in g m o i s t u r e . P e tr o le u m e t h e r
( HS k e l l y s o l v e CM ) was a d d e d t o th e c h lo r o f o r m s o l u t i o n ,
w hereupon b e a u t i f u l y e llo w n e e d l e s fo rm e d , m .p . 7 3 °C .
( 1 3 .5 g . , 8 5 $ ) .
I 4 . p -M e th o x y th 1o p h en o 1 . — G one, s u l f u r i c a c i d
!
j(40 m l .) was d i l u t e d w ith w a te r (320 m l .) an d 41 g .
|(0 .3 3 m o le) o f p - a n i s i d i n e was d i s s o l v e d i n t h i s warm a c i d
I [
S o l u t i o n . T h is s o l u t i o n was c o o le d i n a n i c e - b a t h and t h e n j
300 g . o f i c e was a d d e d . The m ix tu r e was s t i r r e d v ig o ro u s ly !
i ’ !
’ a n d a s o l u t i o n o f 25 g . o f sodium n i t r i t e i n 100 m l. w a te r j
1 ..... •■■■■•................... I
was a d d e d . The r e s u l t i n g s o l u t i o n was t e s t e d w ith p o ta s s iu iri
I ' - ■ . . . . , . ^
; . *
i i o d i d e - s t a r e h p a p e r t o d e te r m in e when e x c e s s n i t r o u s a c i d
was p r e s e n t . The a d d i t i o n o f n i t r i t e was c o n t i n u e d u n t i l
i
jthe s o l u t i o n , a f t e r th o r o u g h s t i r r i n g a n d s t a n d i n g 15 t o 20
jse c o n d s , p ro d u c e d a n im m e d ia te b l u e c o l o r w ith th e t e s t
!
p a p e r . To t h i s s o l u t i o n , en o ugh sodium a c e t a t e was now
|
jadded t o n e u t r a l i z e t h e f r e e a c i d .
I n a 2 - 1 . , 3 - n e c k e d f l a s k , e q u ip p e d w ith a
m e c h a n ic a l s t i r r e r , d ro p p in g f u n n e l , an d e x h a u s t tu b e t o th e
h o o d , was p l a c e d a s o l u t i o n o f 100 g . ( 0 .6 3 m o le) o f
p o ta s s iu m e t h y l x a n t h a t e i n 250 m l. o f w a t e r . To t h i s
s o l u t i o n , k e p t a t 70 t o 8 0 °C * , was a d d e d s lo w ly w ith
v ig o r o u s s t i r r i n g a c o l d s o l u t i o n c o n t a i n i n g 4 1 g . o f th e
above d i a z o t i z e d p - a n i s i d i n e . S t i r r i n g a n d h e a t i n g w ere
{ c o n tin u e d f o r a b o u t one h o u r a f t e r th e a d d i t i o n o f th e
jdiazonium s o l u t i o n . The d a rk o i l was rem o v ed fro m t h e
c o o le d s o l u t i o n a n d t h e a q u e o u s l a y e r e x t r a c t e d w ith e t h e r ,
t h e p r o d u c t o b t a i n e d b e in g co m b in ed w ith t h a t f i r s t re m o v e d .
34 1
T h is m a t e r i a l was t h e n r e f l u x e d f o r 3 h o u r s w i t h a s o l u t i o n j
o f 38 g . ( 0 . 6 8 m o le) o f p o ta s s iu m h y d r o x id e i n 670 m l. o f
'35$ e t h a n o l , t o w h ic h h a d b e e n a d d ed 7 g . o f g l u c o s e . The
a lc o h o l was rem o v ed by d i s t i l l a t i o n u n t i l t h e r e s i d u a l
volum e was a b o u t 100 m l. T h is was a c i d i f i e d w ith c o l d
d i l u t e s u l f u r i c a c i d , a few g . o f z in c d u s t was a d d e d , a n d
i . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ' ' ’ . . . . . . . . . . . . . '
th e o i l y t h i o l was rem o v ed by d i s t i l l a t i o n w ith s te a m . The
i i s t i l l a t e was e x t r a c t e d w ith e t h e r , t h e e t h e r d r i e d o v e r
s a lc iu m c h l o r i d e , an d t h e o i l r e m a in in g a f t e r d i s t i l l a t i o n
Df th e e t h e r was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e . The
y i e l d was 35 g . ( 7 9 $ ) . B .p . 8 8 -9 0 ° C . a t 5 mm. Hg.
5 • E t h y l 3 ,5 * » d in itr o - 4 - ( p - m e th o x y th io p h e n o x y ) -
'a y d ro c in n a m a te . — E t h y l 4 - h y d r o x y - 3 ,5 - d i n i t r o h y d r o c i n n a m a t e
( 5 .7 g . , 0 .0 2 m o le ) a n d t o l u e n e - p - s u l f o n y l c h l o r i d e ( 3 . 8 g . ,
0 . 0 2 m o le) w ere h e a t e d on t h e s t e a m - b a t h w ith p y r i d i n e
(50 m l .) f o r t e n m i n u t e s . p - M e th o x y th io p h e n o l (4 * 2 g . ,
0 .0 3 m o le ) was a d d e d a n d t h e s o l u t i o n h e a t e d u n d e r r e f l u x
f o r one h o u r . The p y r i d i n e was t h e n rem oved u n d e r r e d u c e d
p r e s s u r e a n d e t h a n o l (50 m l . , 95$) was a d d e d t o th e r e s i d u a l
gum. A y e ll o w p r e c i p i t a t e a p p e a re d a f t e r a d d i t i o n o f w a te r
and t h i s was c o l l e c t e d . The y e llo w c r y s t a l s , m .p . 8 5 ° C .,
were th e d e s i r e d p r o d u c t ( 7 .8 g . , 9 6 $ ) .
A n a l. C a lc d . f o r C1 8 H1 8 07 N2 Sj C, 5 3 .2 0 ; H, 4 .4 4 ;
N, 6 . 9 0 ; S , 7 . 8 6 . F ound; C, 5 3 .1 5 ; H, 4 .5 9 ; N, 7 .0 0 ;
S, 7 . 4 3 .
i 35 |
j I
! 6* E th y l 5 ,5 - d iio d o - 4 - ( p - m e t h o x y t h io p h e n o x y ) - j
a y d r o c in n a m a te . — E t h y l 3 ,5 - d i n i t r o - 4 - ( p - m e t h o x y t h i o p h e n o x y ) -
a y d ro c in n a m a te (4 g . , 0*01 m o le) was d i s s o l v e d i n a c e t i c
k c i d ( 1 0 0 m l* , g l a c . ) and h y d r o g e n a te d a t room t e m p e r a tu r e
! ; . ■ " .......................................................
a n d a t a p r e s s u r e o f 45 p * s * i* o v e r p a l l a d i z e d c h a r c o a l |
( 5 $ , 2 g * ) . The d ia m in e s o l u t i o n was f i l t e r e d and a d d e d
jdropw ise d u r i n g 30 m in* t o a s t i r r e d s o l u t i o n o f sodium
n i t r i t e (3 *4 g * , 0*05 m o le) i n a c e t i c a c i d (100 m l . , g la c * )
i
an d s u l f u r i c a c i d (1 0 0 m l . , c o n c .) a t 0°C* A f t e r s t i r r i n g
i ; '
lone m ore h o u r , th e t e t r a z o n i u m s a l t s o l u t i o n was a d d e d
! ' ' .......
Sslowly t o a s t i r r e d m ix t u r e o f s o l u t i o n o f i o d in e ( 1 0 g . ,
p . 04 m o le ) a n d so d iu m i o d id e (15 g * , 0*1 m o le) i n w a te r
! ( 2 0 0 m l*) a n d c h lo r o f o r m ( 2 0 0 m l * ) , w h ile t h e t e m p e r a t u r e
i " ' ' ''.......................................
jwas k e p t b e lo w 40°C* The r e a c t i o n m ix t u r e was l e t s t a n d
lover n i g h t a n d a c h o c o l a t e - l i k e r e s i d u e r e s u l t e d * T h is was
^ d isso lv e d i n c h lo r o f o r m ( 2 0 0 m l .) an d w ash ed w ith a q u eo u s
j - . : . . ' ........ ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. .. .. .. .. .. .. .. .. ■ • ■ .... ... ... ... ... ... ... ■ • . . . . . I
! - \ !
so d iu m m e t a b i s u l f i t e u n t i l t h e s o l u t i o n t u r n e d t o a y e llo w -
jorange c o lo r * The c h lo r o f o r m was e v a p o r a t e d t o d r y n e s s an d
|the r e s i d u e was d i s s o l v e d i n b e n z e n e (50 m l*) an d
jc h ro m ato g rap h e d on a colum n o f a lu m in a . E l u t i o n was
iach iev ed by u s i n g a s o l u t i o n o f m e th a n o l ( 1 0 $ ) i n b e n z e n e
; (
iand t h e e l u a t e was c o n c e n t r a t e d t o 10 m l. A d d i t io n o f
|................ .................................................... . .....................................- j
p e tr o le u m e t h e r ( ,fs k e l l y s o l v e Cw)« c a u s e d t h e s e p a r a t i o n o f j
..................................... j
bhe d e s i r e d e s t e r a s w h ite f l u f f y c r y s t a l s , m .p*
1 0 7 -1 0 7 *5°C . ( 2 .9 g . , 5 1 $ ) .
36
| A n a l. C a lc d . f o r 028^18^3*^2* C, 3 8 .0 3 ; H, 3 * 1 8 ;
I , 4 4 .6 9 * Found; C, 3 8 .5 0 ; H, 3 . 3 5 ; I , 4 3 .3 6 .
7 . 5 ,5 - D iio d o - 4 - ( p - m e th o x y th lo p h e n o x y ) -
h y d ro c in n a m io A c id . — E t h y l - 3 , 5 - d i i o d o - 4 - ( 4 ' -
m e th o x y th io p h e n o x y ) -h y d ro c in n a m a te ( 2 .2 7 g . , 0 .0 0 4 m o l e ) ,
d i s s o l v e d i n a c e t i c a c i d (25 m l . , g l a c . ) a n d h y d r o c h l o r i c
a c i d ( 2 0 m l . , c o n c . ) , was h e a t e d u n d e r r e f l u x f o r one h o u r .
On c o o l i n g , th e d e s i r e d a c i d s e p a r a t e d a s w h ite f l u f f y
c r y s t a l s , m .p . 1 5 3 -1 5 4 °C . ( 2 .1 5 g . , 1 0 0 $ ) . The compound
o b t a i n e d i s b e l i e v e d t o b e 3 , 5 - d i i o d o - 4 -
!( p -m e th o x y th io p h e n o x y )-h y d ro c in n a m ic a c i d an d h a s b e e n
| " " '
s u b m i tt e d f o r a n a l y s i s .
8 . T re a tm e n t o f E t h y l 5 , 5 - D i l o d o - 4 -
( p -m e th o x y th io p h e n o x y ) -h y d r o c in n a m a te w i t h H y d r lo d ic an d
A c e t i c A c i d s . - - E t h y l 3 ,5 - d i io d o - 4 - ( p - m e th o x y th .io p h e n o x y ) -
'a y d ro c in n a m a te ( 1 .6 2 g . , 0 .0 0 3 m o le) was d i s s o l v e d i n a 1 ;1
m ix t u r e o f g l a c i a l a c e t i c a c i d an d h y d r l o d i c a c i d (4 7 $ ,
L5 m l . ) a n d was h e a t e d u n d e r r e f l u x f o r one h o u r . On
s o o l i n g , a c r y s t a l l i n e p r o d u c t was O b ta in e d , m .p . 182 °C .
( 1 .7 g . , 8 7 $ , b a s e d u p o n th e s t r u c t u r e p re su m e d b e lo w ) .
A n a l y s i s o f t h i s p r o d u c t f o r i o d in e s u g g e s t s t h a t i t i s a
t r i i o d o d e r i v a t i v e , p re s u m a b ly 3 , 5 - d i i o d o - 4 - ( 4 ’-h y d r o x y - 3
L o d o th io p h e n o x y )-h y d ro c in n a m ic a c i d .
! 37
I
i
! 3 , 5 - D i n i t r o - L - t y r o s i n e . — L - T y r o s in e ( 1 0 .5 g . ,
0 .0 5 8 m o le ) was d i s s o l v e d i n 45 m l. c o n c . s u l f u r i c a c i d ,
k e e p in g t h e te m p e r a t u r e b e lo w 10 °C. The s o l u t i o n was
c o o le d t o -5 ° G . and 8 .5 m l. n i t r i c a c id (d = 1 .4 2 ) was added
! ■ '■ ' ' - ....................................................................................................
[d ro p w ise , w i t h s t i r r i n g , d u r i n g a p e r i o d o f one a n d o n e - h a l f
\
tio u r, k e e p in g t h e te m p e r a t u r e a lw a y s b e lo w 0 °G . V¥hen a l l
th e n i t r i c a c i d was a d d e d , t h e s o l u t i o n was s t i r r e d 15 m in .
a t 0 ° C . a n d t h e n p o u r e d i n 200 g . i c e . A c o o l e d , c o n c .
s o l u t i o n o f sodium h y d r o x id e (40 g . ) was p o u r e d s lo w ly i n t o
th e i c e m i x t u r e , s t i r r e d , r e f r i g e r a t e d o v e r n i g h t , an d
I ............................................ .. ........................................... ■ " " ’ |
j f i l t e r e d . The y e llo w - o r a n g e p r e c i p i t a t e o b t a i n e d was j
Jwashed w ith w ater and d r ie d . R e c r y s t a lliz a t io n from w ater I
I " ■ .......‘ ' " ‘ i
y i e l d e d 1 4 .6 g . {87%) o f th e d e s i r e d p r o d u c t , m .p . I
2 3 0 -2 3 2 °C. ( d e c . ) .
1 0 . 5 , 5 - D i n l t r o - N - a c e t y l - L - t y r o s i n e . — 3 , 5 - D i n i t r o -
t y r o s in e ( 7 . 0 g . ) was su sp en d e d i n 42 m l. o f w a te r and
4 .5 g . o f sod ium h y d r o x id e d i s s o l v e d i n 14 m l. o f w a te r was
a d d e d , k e e p in g th e te m p e r a tu r e a t 20°G . A c e t ic a n h y d r id e
(3.6 ml.) was a d d e d , s l o w l y , w h ile s t i r r i n g , w ith o u t r a i s i n g
th e te m p e r a tu r e ab ove 2 0 °C . The s o l u t i o n was s t i r r e d one
h ou r m ore a t room te m p e r a tu r e and s t i r r e d 3 0 m in . m ore a t
40°C . I t was c o o le d t o 1 0 °C . and 5N h y d r o c h lo r ic a c id was
a d d ed , d r o p w ise t o pH 3. The y e llo w p r e c i p i t a t e was w ashed
Jand d r ie d , m.p. 1 8 9 -1 9 0 °C . (6.7 g . , 8 2 $ ) .
3 8
1 1 . E t h y l 5 . 5 - P i n i t r o - N - a c e t y l - L - t y r o s i n a t e . —
3 , 5 - D i n i t r o - N - a c e t y l - L - t y r o s i n e ( 2 .5 g . ) was d i s s o l v e d i n
32 m l. e t h a n o l (100$) a n d t h e s o l u t i o n f i l t e r e d t o rem ove
i n o r g a n i c s a l t s . A c e ty l c h l o r i d e ( 1 .3 g . ) was s lo w ly a d d e d |
an d t h e s o l u t i o n r e f l u x e d f o r one h o u r . The s o l v e n t was !
J ..... ‘ ’ * ‘ ' ‘ ' " " ’ ’ ‘ ’ |
a s p i r a t e d a n d t h e r e s i d u e r e d i s s o l v e d i n a minimum o f h o t j
< 3t h a n o l ( 9 5 $ ) . The s o l u t i o n was c o o le d a n d t h e w a l l s o f th e j
(c o n ta in e r s c r a t c h e d u n t i l c r y s t a l l i z a t i o n s t a r t e d . The |
( c r y s ta l s w ere c o l l e c t e d a n d d r i e d ( 2 .3 4 g . , 8 6 $ ) , m .p .
I l2 0 -1 2 1 oC •
j
I t
| 1 2 . 3 , 5 - D i n l t r o - 4 - ( p -m e th o x y th lo p h e n o x y ) - H - a c e t y l - j
L - p h e n y l a l a n i n e E t h y l E s t e r . - - E t h y l 3 , 5 - d i n l t r o - N - a c e t y l - L - |
jb y r o s in a te ( 6 . 8 g . , 0 . 0 2 m o le ) a n d t o l u e n e - p - s u l f o n y l
!
c h l o r i d e ( 3 . 8 g . , 0 .0 2 m o le ) w ere h e a t e d on t h e s t e a m - b a t h
w ith p y r i d i n e (50 m l . ) , f o r 10 m in . p - M e th o x y th io p h e n o l
( 4 . 2 g . , 0 .0 3 m o le ) was a d d e d an d t h e s o l u t i o n h e a t e d u n d e r
r e f l u x f o r one h o u r . The p y r i d i n e was t h e n rem oved u n d e r
r e d u c e d p r e s s u r e an d e t h a n o l (50 m l . , 95$) a d d e d t o th e
r e s i d u a l gum. The a l c o h o l i c s o l u t i o n was d i l u t e d w i t h w a te r
(100 m l .) a n d e x t r a c t e d w i t h c h lo r o f o r m . The e x t r a c t s w ere
w ash ed , by e x t r a c t i o n , w i t h tw o 2 0 m l. p o r t i o n s o f w a te r and
B v a p o ra te d t o a brow n gum. The gum was d i s s o l v e d i n b e n z e n e
and c h ro m a to g ra p h e d on a colum n o f s i l i c a g e l . E l u t i o n was
a c h ie v e d by u s i n g b e n z e n e , a n d th e e l u a t e was e v a p o r a t e d t o
a y e llo w - o r a n g e gum. The gum was r e f r i g e r a t e d f o r t h r e e
ih o u rs a n d y e ll o w c r y s t a l s , m .p . 1 4 6 .5 - 1 4 7 .5 ° C . , r e s u l t e d
( 4 .6 3 g . , 50% ).
A n a l . C a lc d . f o r 0 2 0 ^ 2 1 0 8 ^ 3 ^* 0 , 5 1 .9 0 ; H, 4 .5 0 ;
N, 9 * 1 0 ; S , 6 . 9 0 . Found* G, 5 1 .8 8 ; H, 4 . 7 0 ; N, 9 .4 0 ;
S , 6 .6 2 . I
i I
! ■ ■ ■ ■- ' ' !
! I
13* 2 ,4 - D ln it r o p h e p y l p -Meth o x y p h e n y l S u l f i d e . — I n
a 2 - 1 . 3 -n e c k e d f l a s k , e q u ip p e d w ith s t i r r e r and
th e rm o m e ter , was p la c e d i n a s o l u t i o n o f
2 , 4 - d i n i t r o b e n z e n e s u l f e n y l c h l o r i d e ( 5 1 .6 g . , 0 .2 5 m o le) i n
d r y e t h y l e n e c h l o r i d e ( 1 0 0 0 m l .) a n d , t o t h i s s o l u t i o n ,
i ' ‘ ......... .•... ■ ’ . ’ ’ ’ 7 ,
a n i s o l e (1 0 8 m l . , 1 m o le ) was a d d e d . The s o l u t i o n was
s t i r r e d an d c o o le d t o - 5 ° C . To t h i s c o o le d s o l u t i o n ,
a n h y d ro u s alum inum c h l o r i d e (40 g « , 0 . 3 m o le) was a d d e d .
The r e a c t i o n m ix tu r e was t e s t e d w ith p o t a s s i u m i o d i d e - s t a r c h
p a p e r an d a n e g a t i v e t e s t i n d i c a t e d t h e c o m p le tio n o f th e
r e a c t i o n . E th a n o l {95%a 250 m l .) was a d d e d a n d th e s o l u t i o n
was w ash ed w ith two 100 m l . - p o r t i o n s o f w a t e r . The e t h y l e n e
c h l o r i d e was rem o v ed u n d e r r e d u c e d p r e s s u r e a n d a t h i c k
b ro w n ish o i l r e s u l t e d . The o i l was d i s s o l v e d i n b e n z e n e and
c h ro m a to g ra p h e d t h r o u g h a colum n o f a lu m in a . E l u t i o n was
a c h ie v e d by u s i n g b e n z e n e . The e l u a t e was e v a p o r a t e d to a
gummy r e s i d u e u n d e r r e d u c e d p r e s s u r e . E th a n o l ( a b s . ,
2 0 m l .) was a d d e d t o t h e gum o b t a i n e d a n d t h e m ix tu r e was
r e f r i g e r a t e d f o r s e v e r a l h o u r s , w h ereu p o n c r y s t a l l i z a t i o n
o c c u r r e d . R e c r y s t a l l i z a t i o n fro m a b s . e t h a n o l g a v e 58 g .
j(85$) o f th e d e s i r e d p r o d u e t , m .p . 1 1 9 -1 2 0 °C.
1 4 . An a tt e m p t e d s y n t h e s i s o f p - m e th o x y th io p h e n o l
jby c le a v a g e o f 2 ,4 - d i n i t r o p h e n y l ,p - m e t h o x y p h e n y l s u l f i d e . —
|
j 2 ,4 - D i n it r o p h e n y l p -m e th o x y p h e n y l s u l f i d e (3 g . , 0 .0 1 m ole)
was s u s p e n d e d i n a s o l u t i o n o f sodium m e th o x id e ( 1 * 2 g . ,
t
0*02 m ole) in m ethanol (50 m l.) and the m ixtu re was r e flu x e d
Jfor s e v e r a l hours to form a red s o lu t io n . The s o lu t io n was
[concentrated to 20 m l. and c o o le d . Ic e was added to a
volume o f 80 m l., ca u sin g a y e llo w p r e c ip it a t e to appear.
The m ix t u r e was f i l t e r e d . The y e llo w s o l i d , m .p . 8 8 - 8 9 ° C .,
Upon t r e a t m e n t w i t h h y d r i o d i c a c i d , g a v e a d e r i v a t i v e , m .p .
114 °G . ( L i t . , 2 , 4 - d i n i t r o a n i s o l e , m*P* 8 9 ° C .; 2 , 4 -
j d i n i t r o p h e n o l , m .p . 1 1 4 °C • ) • The f i l t r a t e was t h e n c . r
|a c i d i f i e d w i t h h y d r o c h l o r i c a c i d a n d e x t r a c t e d w ith e t h e r .
The e t h e r e x t r a c t g av e hrow n s t a r - l i k e c r y s t a l s , w h ich w ere
Isu b lim ed , y i e l d i n g a p a l e - y e l l o w c r y s t a l l i n e p r o d u c t , m .p .
1 1 4 ° G ., w h ic h , u p o n b r o m i n a t i o n , g a v e a d e r i v a t i v e , m .p .
118°G . ( L i t . , 2 , 4 - d i n i t r o p h e n o l , m .p . 1 1 4 ° C .; 2 , 4 - d i n i t r o -
6 -b ro m o p h e n o l, m .p . 1 1 8 ° G .) . Upon a c i d i f i c a t i o n o f th e
f i l t r a t e , a c h a r a c t e r i s t i c o d o r o f t h i o p h e n o l was n o t e d , b u t
th e d e s i r e d p - m e th o x y th io p h e n o l c o u ld n o t be i s o l a t e d .
1 5 . 2 , 6 - D l i 3 0 p r o p y l - 4 - n i t r o 3 o p h e n o l . — I n a
o n e - l i t e r 3 - n e c k e d f l a s k , f i t t e d w i t h s t i r r e r , th e r m o m e te r,
a n d d ro p p in g f u n n e l , 2 , 6 - d i i s o p r o p y l p h e n o l ( 3 5 .6 g . ,
0 . 2 m o le ) was d i s s o l v e d i n 250 m l. e t h a n o l
C o n c e n t r a t e d h y d r o c h l o r i c a c i d (50; m l*) was a d d e d a n d th e
s o l u t i o n was c h i l l e d t o -5 ° C . A s o l u t i o n o f sod ium n i t r i t e
(15 g . ) i n w a t e r (50 m l* ) was a d d e d d ro p w ls e fro m th e
‘ d r o p p in g f u n n e l d u r i n g 3 h o u r s w h ile t h e s o l u t i o n was t ' I
[ s t i r r i n g . The r e a c t i o n m ix tu r e was p o u r e d i n t o two l i t e r s
o f l c e - w a t e r m ix tu r e a n d r e f r i g e r a t e d f o r f o u r h o u rs * The
m ix tu r e was f i l t e r e d a n d w ash ed w i t h w a te r* The y e llo w
j s o lid was d r i e d a t room t e m p e r a t u r e and r e c r y s t a l l i z e d from
b en zen e* B e a u t i f u l y e ll o w p l a t e s , m .p* 1 6 3 -1 6 3 * 5 °C * , w ere
o b t a i n e d (38* 9 g . , 9 4 $ )*
A n a l* C alcd * f o r GigH^yOgN? C, 6 9 .6 0 ; H, 8*22*
F ound ; C, 6 9 * 1 8 ; H , 8*12*
16* 2 ,6 - D i l s o p r o p y l - 4 - h y d r o x y p h e n o l »—
2 , 6 - D i i s o p r o p y l - 4 - n i t r o s o p h e n o l ( 2 0 .7 g . , 0*1 m o le ) was
d i s s o l v e d i n d ry e t h y l e t h e r ( 2 0 0 m l*) a n d was h y d r o g e n a te d
jat room te m p e r a t u r e a n d 25 p . s * i * o v e r f r e s h l y a c t i v a t e d
R a n e y - n ic k e l c a t a l y s t (3 g * )* A f t e r a b o u t two h o u r s , th e
p r e s s u r e d ro p p e d t o a minimum ( a b o u t 16 p . s . i . ) , w h ich
j i n d i c a t e d t h e c o m p le tio n o f t h e r e d u c t i o n , a n d t h e m ix tu r e
jwas f i l t e r e d i n an a tm o s p h e re o f c a rb o n d io x id e * To t h i s
• f i l t r a t e , c o n c . h y d r o c h l o r i c a c i d ( 2 0 m l . , 0 * 2 m o le ) was
jadded s lo w ly an d a w h ite p r e c i p i t a t e was form ed* T h is
i n t e r m e d i a t e , p -a m in o p h e n o l h y d r o c h l o r i d e , was d i s s o l v e d i n
s t h a n o l (100 m l . , 95$) an d d i l u t e d t o 300 m l. w i t h w a t e r .
T his s o l u t i o n was a d d e d s lo w ly t o a s o l u t i o n o f f e r r i c
42
m l .) w ith
| • ' r ' • C " •
s t i r r i n g a t 6 0 °C. The r e s u l t i n g s o l u t i o n was s te a m -
j i i s t i l l e d an d t h e d i s t i l l a t e was e x t r a c t e d w i t h e t h e r . The
'
e t h e r e x t r a c t was s h a k e n w i t h a n a q u e o u s s o l u t i o n o f sod ium
i
I
h y d r o s u l f i t e s e v e r a l tim e s u n t i l t h e e t h e r e x t r a c t was
<
i
^ d e c o lo r iz e d . The e t h e r was rem oved a n d a c ru d e p r o d u c t ,
i -
jl3 .6 g . , was o b t a i n e d . The c ru d e p r o d u c t was d i s s o l v e d i n
j ’
'd i l u t e sodium h y d r o x id e s o l u t i o n , f i l t e r e d , a n d a c i d i f i e d
i
i
jw ith so diu m h y d r o s u l f i t e . The c o l o r l e s s c r y s t a l l i n e
! i
I |
m a t e r i a l (11 g . , 57%), m .p . 1 0 7 ° C ., was th e p r o d u c t d e s i r e d j
‘S ' . - !
jfor t h e n e x t c o n v e r s i o n .
1 7 • E th y l 5 , 5 - d i n i t r o - 4 - (5 *,5 t - d i l s o p r o p y l - 4
h y d ro x y p h e n o x y ) - h y d r o c l n n a m a te « -- E t h y l 4 - h y d r o x y - 3 , 5 -
j
d i n it r o h y d r o c i n n a m a te (5*7 g . , 0 .0 2 m o le) a n d t o lu e n e - p »
s u l f o n y l c h l o r i d e ( 3 .8 g . , 0.G 2 m o le ) w ere h e a t e d on th e
s t e a m - b a t h w i t h p y r i d i n e (50 m l .) f o r t e n m i n u t e s .
2 ,6 - D i i s o p r o p y l - 4 - h y d r o x y p h e n o l ( 3 .9 g . , 0 .0 2 m o le ) was
I
a d d ed and t h e s o l u t i o n h e a t e d u n d e r r e f l u x f o r one h o u r .
The p y r i d i n e was t h e n rem o v ed u n d e r r e d u c e d p r e s s u r e a n d
e t h a n o l (50 m l . , 95$) a d d e d t o t h e r e s i d u a l gum. The
a l c o h o l i c s o l u t i o n was d i l u t e d w i t h w a te r ( 1 0 0 m l.) an d
e x t r a c t e d w i t h c h lo r o f o r m . The e x t r a c t s w ere s h a k e n w ith
tw o 2 0 m l. p o r t i o n s o f w a te r a n d e v a p o r a t e d t o fo rm a gum.
The gum was d i s s o l v e d i n b e n z e n e a n d c h ro m a to g ra p h e d on a
colum n o f a lu m in a . E l u t i o n was a c h i e v e d by u s i n g b e n z e n e
c h l o r i d e (24*6 g . , 0 .1 5 m o le ) i n w a te r
""...................: ~ ” 43
a n d th© e l u a t e was a s p i r a t e d t o a s m a ll v o lu m e • Upon
a d d i t i o n o f p e tr o le u m e t h e r t o t h i s t h i c k l i q u i d , a y e llo w
c r y s t a l l i n e p r o d u c t ( 5 .3 8 g . , 5 9 $ ) , m .p . 9 7 . 5 - 9 8 . 5 ° C . , was
o b ta in e d *
A n a l . C alcd* f o r CggHggOgNg? C, 6 0 .0 0 ; H , 6 * 1 0 ;
IN, 6 .1 0 . Found? C, 5 9 .8 9 ; H, 6 * 2 0 ; N, 6 .0 8 .
18* 4 ,4 ^ D lm e th o x y d ip h e n y llo d o n iu m I o d id e . — I n a
p n e - l i t e r t h r e e - n e c k e d f l a s k , f i t t e d w i t h a s t i r r e r ,
!
i '
th e r m o m e te r , a n d d r o p p in g f u n n e l , t h e r e was p l a c e d a m ix tu r e
o f p o ta s s iu m i o d a t e ( 2 1 .4 g . , 0 * 1 m o l e ) , a c e t i c a c i d
|( 100 m l . , g l a c i a l ) , a n d a c e t i c a n h y d rid e (100 m l . ) . The
m ix tu re was c h i l l e d t o b e lo w lO °G . an d a s o l u t i o n o f a n i s o l e
(50 m l .) i n a c e t i c a n h y d r id e (50 m l .) land s u l f u r i c a c i d
(25 m l . , c o n c .) was a d d e d d r o p w is e , d u r i n g one h o u r , w i t h
c o n s t a n t s t i r r i n g . The r e a c t i o n m ix t u r e was s t i r r e d
o v e r n i g h t a t room te m p e r a t u r e a n d t h e n p o u r e d on l e e - w a t e r
m ix tu r e (500 m l . ) . The m ix t u r e was e x t r a c t e d w i t h two
1 0 0 m l . p o r t i o n s o f c h lo r o f o r m , w h ich w ere com b ined an d
e v a p o r a t e d t o d r y n e s s . S u b l i m a t io n o f t h e r e s i d u e , h o w e v e r,
gave o n ly c o l o r l e s s n e e d l e s , m .p . 4 9 -5 0 ° C * , w h ich a r e
u n d o u b te d ly t h o s e o f p - h y d r o x y a n i s o l e (m .p . 5 3 ° C . ) .
I f t h e a q u e o u s s o l u t i o n fro m t h e above p r e p a r a t i o n
i s d a r k , i t was c h a r c o a l e d , f i l t e r e d and t h e n t o i t was
a d d ed an a q u eo u s s o l u t i o n o f sodium i o d i d e (10 g . ) . T h is
c a u s e d p r e c i p i t a t i o n o f a y e ll o w s o l i d , w h ich was c o l l e c t e d
44
an d d r i e d , g i v i n g - 9 * 5 -g. (2 0 $ ) o f p r o d u c t , m .p . 184° [ t h e
r e p o r t e d y i e l d i s 5 . 2 g . ( 1 1 $ ) , m .p . 1 7 9 -1 8 2 ° ( 6 ) ] .
1 9 . 5 , 5 - B ilo d o - L - r T y r o s in e . — P o w dered i o d i n e (56 g . )
was s u s p e n d e d i n a s o l u t i o n o f t y r o s i n e (40 g . ) i n g l a c i a l
a c e t i c a c i d (280 m l .) a n d 36 N h y d r o c h l o r i c a c i d (160 m l .) *
T h i r t y p e r c e n t h y d ro g e n p e r o x id e s o l u t i o n was t h e n a d d ed i n
s m a ll p o r t i o n s , w ith s h a k i n g , d u r i n g f i v e m in u te s u n t i l th e
i o d i n e c o l o r h a d d i s a p p e a r e d . The t e m p e r a t u r e o f th e
r e a c t i o n was m a i n t a i n e d a t 60-65°C * The y e ll o w s o l u t i o n was
th e n c o o le d an d d i l u t e d s u c c e s s i v e l y w i t h w a te r ( 2 0 0 m l . ) ,
b .8 8 0 M ammonia s o l u t i o n (180 m l . ) , an d 10$ sodium h y d ro g e n
/
s u l f i t e s o l u t i o n (100 m l . ) . An ammonia s o l u t i o n ( 0 .8 8 0 M)
jwas t h e n a d d e d d ro p w is e u n t i l c r y s t a l l i z a t i o n b e g a n .
3 . 5 - D i i o d o t y r o s i n e s e p a r a t e d a s c o l o r l e s s n e e d l e s . I t was
c o l l e c t e d , w ashed w i t h w a te r a n d a l c o h o l and a i r - d r i e d , m .p*
198° ( 6 8 g . , 7 1 $ ) .
I
' 20* 3 , 5 - D i l o d o - N - a c e t y l - L - t y r o s i n e . — A s o l u t i o n o f
3 .5 - d i l o d o - L - t y r o s i n e ( 8 3 .5 g . ) i n 2 N sodium h y d r o x id e
(835 m l .) was k e p t b e tw e e n 5 ° an d 1 0 ° an d s t i r r e d w h ile
a c e t i c a n h y d rid e (92 m l.) was a d d e d d u r in g one h o u r . A f t e r
b e in g k e p t o v e r n i g h t , t h e s o l u t i o n was t r e a t e d w i t h sodium
h y d r o x id e (40 g . ) i n w a te r (100 m l .) and l e f t a t room
te m p e r a tu r e f o r 3 h o u r s . A f t e r a d d i t i o n o f a l c o h o l
(500 m l .) t h e s o l u t i o n was s t i r r e d a n d a c i d i f i e d t o pH2 by
a d d in g c o n c e n t r a t e d h y d r o c h l o r i c a c i d . The s o l i d was
45 !
c o l l e c t e d a n d w ash ed w i t h w a t e r ; a s e c o n d c ro p was o b t a i n e d
by d i l u t i o n o f t h e f i l t r a t e . The a c e t a m i d o - a c i d ( 6 7 .8 g . ,
74$) m e l t e d a t 1 1 2 -1 T 8 ° G ., a n d was u s e d w i t h o u t f u r t h e r
p u r i f i c a t i o n .
!
2 1 . 5 , 5 - D i i o d o - N - a c e t y l - L - t y r o s i n e E t h y l E s t e r .- - A
m ix t u r e o f 3 , 5 - d i i o d o - N - a c e t y l - L - t y r o s i n e (79 g * j ,
p - t o l u e n e s u l f o n i c a c i d (5 g . ) , e t h a n o l (50 m l . ) , an d
c h lo r o f o r m (500 m l . ) w ere b o i l e d u n d e r r e f l u x f o r 8 h o u r s ,
[water b e in g s e p a r a t e d a u t o m a t i c a l l y fro m t h e a z e o t r o p e .
k f t e r c o o l i n g , t h e s o l u t i o n was w a sh e d w ith sodium h y d ro g e n
[c a rb o n a te s o l u t i o n , t h e n w i t h w a t e r , a n d was e v a p o r a t e d t o
i
d r y n e s s . The r e s i d u a l s o l i d was c r y s t a l l i z e d from a q u eo u s
e t h a n o l c o n t a i n i n g a few d ro p s o f h y d r o c h l o r i c a c i d . The
e t h y l e s t e r was o b t a i n e d a s c o l o r l e s s n e e d l e s ( 5 6 .0 g . ,
| '
j67$), m .p . 1 5 4 -1 5 5 ° e .
2 2 . 5 ,5 - D lio d o - 4 - p - m e th o x y p h e n o x y - N - a c e ty l- L -
t y r o s l n e . - - 4 ,4 '-D lm e th o x y d ip h e n y llo d o n iu m i o d i d e (4®6 g . ,
0 .0 1 m o le) an d e t h y l 3 , 5 - d i i o d o - N - a c e t y l - L - t y r o s i n a t e
( 5 .0 g . , 0 .0 1 m o le ) w ere g ro u n d t o g e t h e r t o a f i n e pow der
w hich was s u s p e n d e d i n a s o l u t i o n o f sodium m e th o x id e
( 0 .5 4 g . , 0 .0 1 m o le) i n m e th a n o l (100 m l . ) . The m ix tu r e was
r e f l u x e d f o r 24 h o u r s . Then i t was f i l t e r e d , w ashed w i t h
w a te r (20 m l . ) , a n d d r i e d , k w h ite c r y s t a l l i n e ( 4 .9 g . ,
80$ y i e l d ) was o b t a i n e d , m .p . 1 9 0 ° ( C a . ) .
46
2 3 . 5 , 5 - B l i o d o - L - t h y r o n i n e . — A m ix t u r e o f
3 , 5 - d i io d o - 4 - p - m e tb .o x y p h e n o x y - N - a c e ty l- L - ty r o s in e (10 g . ) ,
a y d r i o d i c a c i d (5 7 $ , 2 0 m l* ), a n d a c e t i c a c i d (20 m l . , g l a c . )
was r e f l u x e d f o r 4 h o u r s . The s o l u t i o n was e v a p o r a t e d t o
d r y n e s s u n d e r r e d u c e d p r e s s u r e a n d th e r e s i d u e was d i s s o l v e d
i n h o t e t h a n o l (70 m l .) * To t h e b o i l i n g a l c o h o l i c s o l u t i o n
was a d d e d a h o t s o l u t i o n o f so d iu m a c e t a t e ( t r i h y d r a t e ;
15 g . ) a n d sodium m e t a b i s u l f i t e ( 0 .5 g . ) i n w a te r (50 m l . ) ,
k f t e r b e in g l e f t i n t h e r e f r i g e r a t o r f o r a s h o r t t i m e , th e
w h ite c r y s t a l l i n e p r e c i p i t a t e was f i l t e r e d o f f , w ashed w i t h
p ra te r a n d a l c o h o l , and d r i e d . The m a t e r i a l was p u r i f i e d by
jd is s o l v i n g i t i n a l c o h o l c o n t a i n i n g a l i t t l e h y d r o c h l o r i c
a c i d , d e c o l o r i z i n g t h e s o l u t i o n w ith c h a r c o a l , d i l u t i n g w ith
w a te r , a n d p r e c i p i t a t i n g t h e a m in o - a c id by th e a d d i t i o n o f
b o i l i n g sodium a c e t a t e s o l u t i o n . The p r o d u c t was c o l l e c t e d
and d r i e d (7*7 g . , 9 0 $ , m .p . c a . 2 5 0 ° C .) .
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yniversityofSouihern^alifomiirOlBraiv

Asset Metadata

Creator Hu, John Chih-An (author)

Core Title Synthesis of some new analogs of thyroxine

Contributor Digitized by ProQuest (provenance)

Degree Master of Science

Degree Program Chemistry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c17-793855

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Rights Hu, John Chih-An

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