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3-SUBS TITUTSD THIOPHENES

BY w a lte r c .

McCarthy

S ubm itted to th e P a c u lty of the Graduate School i n p a r t i a l f u lf illm e n t of the requirem ents f o r th e d eg ree, D octor of Philosophy, in th e Department of Chem istry, In d ian a U n iv e rsity , A ugust, 1949

ProQuest Number: 10296521

All rights reserved INFORMATION TO ALL USERS The quality o f this reproduction is d e p e n d e n t upon th e quality o f th e c o p y subm itted. In th e unlikely e v e n t that th e author did not sen d a c o m p le te manuscript an d there are missing p a g e s , th e s e will b e n o ted . Also, if material had to b e rem oved , a n o te will in d icate th e d eletion .

uest, ProQuest 10296521 Published by ProQuest LLC (2016). Copyright o f th e Dissertation is held by th e Author. All rights reserved. This work is p ro tected again st unauthorized cop yin g under Title 17, United States C o d e Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346

ACKNOWLEDGEMENT

The a u th o r w ishes to ex p ress h is s in c e re a p p re c i­ a tio n to P ro fe s s o r E. Campaigne f o r h is guidance and encouragem ent d u rin g th e course of t h i s in ­ v e s ti g a t i o n . This o p p o rtu n ity i s tak en to ex p ress th e a u th o r !s in d eb ted n ess to the S te rlin g -W in th ro p Research I n s t i t u t e f o r th e fe llo w sh ip f o r th e y e a rs 1948 and 1949. To my w ife , Mary, t h i s th e s i s i s d e d ic a te d .

TABLE OF CONTENTS

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

1

HISTORICAL..............................................................................................................................

2

A.

M o n o -3 -su b stitu ted th io p h e n e s ..........................................................................

2

B.

Thiophenes as sy m p a th o m im etics......................................................................

3

C.

S tr u c tu r e and sympathomimetic a c t i v i t y .....................................................

5

D.

S tr u c tu r e and p e n i c i l l i n p ro d u ctio n s tim u la n t a c t i v i t y ..................

15

E.

S tr u c tu r e and a n tic o n v u ls a n t a c t i v i t y ..............................................................17

F.

Methods of p re p a ra tio n of amines p re v io u sly used f o r thiophene compounds.................................................................................................... 19

DISCUSSION.................................................................................................................................. 23 A.

B rom ination of 5 -m e th y lth io p h e n e .......................................................................23

B.

P re p a ra tio n of p re v io u sly known compounds.................................................... 27

C.

P re p a ra tio n of new compounds................................................................................. 32

EXPERIMENTAL.............................................................................................................................. 40 A.

B.

Brom ination of 3-m ethyl thiophene

......................................................... 40

1.

S tudy of peroxide c a t a l y s t s ......................................................................... 40

2.

A ttem pted r e a c tio n w ith N -b ro m o p h th alim id e....................................... 42

3.

Phosphorus p e n ta c h lo rid e as h alo g en atin g agent ............................

4.

P re p a ra tio n of 3 -th e n y l brom ide................................................................. 43

5.

A ttem pted r e a c tio n of 2-brom o-5-m ethylthiophene w ith h e x a m ln e ................................................................................................................. 43

43

P re p a ra tio n of p re v io u sly known...compounds.....................................................45 1.

S u c cin im id e ............................................................................................................ 45

2.

N -B rom osuccinim ide........................................................................................... 46

3.

Benzoyl p e r o x i d e ............................................................................................... 46

4.

C obalt n ap h th en ate ....................................................................................... ii

46

C.

5.

N -B ro m o p h th a lim id e.............................................................................................47

6.

H ydrazoic a c i d ..................................................................................................... 47

7.

l-P h e n y l- 2 - n itr o p r o p e n e .................................................................................... 48

8.

l-P h en y l-2 -am in o p ro p an e....................................................................................48

9.

3 -T h e n a ld e h y d e ..................................................................................................... 49

10.

3-^henoic a c i d ..................................................................................................... 50

11.

3 - T h ie n y la c e to n itr ile .........................................................................................51

12.

3 -T h ie n y la c e tic a c i d .........................................................................................51

P re p a ra tio n of new com pounds...............................................................................52 1.

D ie th y l 3 -th en y lm alo nate ...........................................................................

52

2.

3-Thenylm aIonic a c i d ............................................

52

3. ^ - ( 5 - T h ie n y l) - p r o p io n ic a c i d ...................................................................... 53 4 . /^ -(3 -T h ie n y l)-p ro p io n y l c h l o r i d e ............................................................. 53 5. itf- N itro - 3 - v in y lt h i o p h e n e ...............................................................................53 6 . ft - ( 3 - I h ie n y l) -e t h y l a m i n e ...............................................................................54 a.

A ttem pted Dchmidt d e g r a d a t i o n ............................................................ 54

b.

C u rtiu s d e g r a d a t i o n .................................

55

c.

R eduction of c o -n itro -3 -v in y lth io p h e n e ......................................

55

d.

R eduction of 3 - t h i e n y l a c e t o n i t r i l e .................................................... 56

e.

H y d r o c h lo r id e ............................................................................................... 57

f.

Benzoyl d e r i v a t i v e .......................................................................................57

g.

Phenyl th io u re a d e r i v a t i v e ..................................................................... 57

7 . N -B e n z a l-^ -(3 -th ie n y l)-e th y la m in e ........................................................

58

8 . 3 - % ie n y la c e ty l c h lo r id e ................................................................................... 58 9 . N -M e th y l-3 -th ie n y la c e ta m id e .......................................................

iii

58

N-Methyl-y$-( 3 - th i e n y l ) -e th y la m in e ........................................................

59

a.

M eth y latio n of th e S c h if f base . . . . . . . . . . . . .

59

b.

R eduction of IL -m e th y l-3 -th ie n y la c e ta m id e ...............................

59

c.

P h e n y lth io u re a d e r i v a t iv e .................................................................

60

l- ( 3 - T h ie n y l) -2 - n itro p r o p e n e .................................................................

60

3 -1 h ie n y la ceto n e ...........................................................................................

61

a.

P r e p a r a tio n .......................... ....................................................................

61

b.

2 ,4 -P in itro p h e n y lh y d r a z o n e .............................................................

61

c.

Oxime.............................................................................. .............................

62

l - ( 3 -T h ie n y l)-2 -a m in o p ro p a n e .................................................................

62

a.

L eu ck art r e a c t i o n ..................................................................................

62

b.

R eduction of l- ( 3 - t h ie n y l) - 2 - n i tr o p r o p e n e ...............................

63

c.

Benzoyl d e r iv a tiv e ..............................................................................

64

d.

P h e n y lth io u rea d e r iv a tiv e .................................................................

64

1 - ( 3-T hienyl)-2-m ethylam inopropane

65

a.

L euckart r e a c tio n , a lk a lin e h y d ro ly s is ...................................

65

b.

L euckart r e a c tio n , a c id h y d ro ly s is ...........................................

66

c.

P h en y lth io u re a d e r i v a t iv e .................................................................

66

d.

O ther d e r i v a t iv e s ..................................................................................

66

E th y l 3 - th ie n y la c e ta te ..............................................................................

66

N- (2 ^-Hyd r osy e t h y l ) - 3- th i e ny la c e t amid e ...........................................

67

3 -T h ie n y la c e ty lu re a ......................................................................................

68

M ethyl 3 -th e n o a te ...........................................................................................

68

3 -T henhydrazide...............................................................................................

69

N -D im ethyl-3-thenylam ine ..........................................................................

69

3-Thenyl a lc o h o l ...........................................................................................

70

iv

2 2 . 1 - ( 3 - T h ie n y l) - e th a n o l.........................................................................................70 23. l - ( 3 -T hienyl ) - p r o p a n o l .................................................................................... 71 24.

2 - ( 3 - T h e n y l)-im id a z o lin e ...........................................................................

72

25. 3-T henyltrim ethylaim oninm brom ide............................................................... 72 SUMMARY........................................................................................................................................... 73 BIBLIOGRAPHY.............................................................................................................................. 74 V IT A ................................................................................................................................................62

v

INTRODUCTION

1

INTRODUCTION This t h e s i s re p re s e n ts p a r t of a long range re se a rc h program u n d er th e d i r e c t io n of P ro fe s s o r E. Campaigne, in v o lv in g th e p re p a ra tio n of analogues o f p h y s io lo g ic a lly a c tiv e compounds c o n ta in in g the 3s u b s t i t u t e d th iophene r in g , and comparison of th e a c t i v i t i e s th e r e o f , w ith th o se o f the corresp o n d ing 2 - s u b s titu te d th ip h e n e s, and vhLth those of th e benzene analogues ( 1 -4 ) . Many cases have been s tu d ie d i n which a benzene rin g of a physio­ l o g i c a l l y a c tiv e compound has been re p laced by a 2 - s u b s titu te d thiophene r in g .

This l i t e r a t u r e has been th o ro u g h ly reviewed by LeSuer ( 5 ).

G en e ra lly th e p h y s io lo g ic a l a c t i v i t y remained of th e same o rd e r of m agnitude, but sometimes in c re a se d a c t i v i t y , o r decreased a c t i v i t y , was r e p o rte d .

A ll of t h i s p rev io us 7*ork has involved 2 - s u b s titu te d th io p h e n e s;

p re p a ra tio n of th e 3 - s u b s titu te d ones in volved procedures too long and la b o rio u s to be of i n t e r e s t .

However, the work of Campaigne and LeSuer ( l )

has made 3 - s u b s titu te d th ip h en es more r e a d ily a v a ila b le . Sympathomimetic drugs 7jere s e le c te d f o r t h i s in v e s tig a tio n because o f th e rem arkable su ccess th a t has been a tta in e d in c o r r e la tin g physio­ l o g i c a l a c t i v i t y w ith s tr u c t u r e , and because of the wide v a r ie ty of compounds t h a t have been in v e s tig a te d p re v io u sly in th is f i e l d .

HISTORICAL

2

HISTORICAL

A.

M o n o -3 -3 u b stitu ted Thiophenes This f i e l d has been th o ro u g h ly review ed by LeSuer (5^ and e a r l i e r

by S te in k o p f ( 6 ) .

P r io r to th e work of Campaigne and LeSuer, th e fo llo w ­

ing m o n o -3 -su b stitu te d th io p h en es had been p rep ared :

3-m ethylthiophene,

3 -e th y lth io p h e n e , 3 -n -p ro p y lth io p h e n e , 3 -i-p ro p y lth io p h e n e , 3 -nb u ty lth io p h e n e , 3 -c h lo ro th io p h e n e , 3-brom othiophene, 3 -io d o th io p h en e, 3 -n itro th io p h e n e , 3-am inothiophene, 3-aoetam idothiophene, 3-benzam idoth io p h e n e , 3 -th e n o ic a c id , 3 -th e n o y l c h lo r id e , 3-thenam ide, 3 -th en ald eh y d e, 3 , 3 ^ - d ith ie n y l k eto n e, and 3 - th ie n y ls u lfo n y l c h lo r id e . 3-M ethyl thiophene has been com m ercially a v a ila b le r e c e n tly , being produced on a p i l o t p la n t s c a le by th e Socony-Vacuum O il Company, from iso p e n ta n e and s u lf u r ( 7 ) .

Campaigne and LeSuer succeeded in brom inating

th i s compound in th e m ethyl group, using th e peroxide c a ta ly z e d r e a c tio n w ith N-brom osuccinim ide ( l ) .

With th is u s e fu l in te rm e d ia te , 3 -th e n y l

brom ide, th u s r e a d ily a v a ila b le , most d e s ire d s id e chains a re f a i r l y a c c e s s ib le th ro u g h sim ple r e a c tio n s . A lthough D ittm er f i r s t re p o rte d (15) th a t 3-m ethylthiophene could n o t be brom inated in th e s id e ch ain , u sin g N-brom osuccinim ide, w ith o u t f i r s t brom inating th e r in g , he su b seq u en tly r e in v e s tig a te d the r e a c tio n , and confirm ed (1 6 ,1 7 ) th e work of Campaigne and LeSuer.

3

B.

Thiophenes as sympathomimetics A number of th iophene compounds have been p rep ared and te s te d f o r

sympathomimetic a c t i v i t y :

)B -(2 -th ie n y l)-e th y la m in e ( I ) ( 8 ,9 ,1 0 ) ,

N -m eth y l-£ -(2-th ie n y l) - e th y la m in e ( I I ) (1 0 ), ^ ( 2 - th ie n y l) - is o p r o p y la m in e ( I I I ) (1 0 ,1 1 ,1 2 ,1 3 ), N -m eth y l-^-(2 “ th ie n y l)-iso p ro p y la m in e (IV) (1 0 ), and 2 -(2 -th ie n y l)-3 -a m in o b u ta n e (V) (1 1 ,1 2 ).

A ll of th e above f iv e compounds have been shown to produce p re s s o r resp o n ses ap p ro x im ate ly e q u iv a le n t to th o se of t h e i r benzene a n a lo g u e s . However, H I i s l e s s a c tiv e th a n i t s benzene analogue as a c ir c u l a to r y s tim u la n t, and as a c e n t r a l nervous system s tim u la n t (1 3 ).

I t i s of

i n t e r e s t t h a t I I I and V a re only h a l f as to x ic as t h e i r benzene analogues ( 12) . Van Zoeren ( l l ) , in h is p a te n t, has d e sc rib e d s e v e ra l o th e r compounds: 2 -(2 -th ie n y l)-l" -a m in o -2 -p ro p a n o l, 2-me th y la m in o -5 -(2 -th ie n y l)-b u ta n e , 3-am in o -2 -(2 “ th ie n y l)- p e n ta n e , 2 -a m in o -l-(2 -th ie n y l)-3 -p h e n y lp ro p a n e , 3 -a m in o -2 -(2 -th ie n y l)-h e x a n e , l-m e th y la m in o -2 -(2 -th ie n y l)-2 -p ro p a n o l, l-m eth y lam in o -2 -(2 “ th ie n y l)- 2 - p e n ta n o l, 3-am ino-2-(2 - th ie n y l) - 2 - p e n ta n o l, l-m e th y la m in o -2 -(2 -th ie n y l)-p ro p a n e , and l-a m in o -2 -(2 -th ie n y l)-p ro p a n e .

4

However* no p h y s io lo g ic a l d a ta i s r e p o rte d . HLicke and S h ee ts (14) have p rep ared 2 -(£ -th ia n a p h th e n y lm e th y l)im id a z o lin e and

OH

XAJH -

i

x

2 -(3 -th ia n a p h th e n y lm e th y l)-iiiiid a z o lin e (VI) and su b m itted them f o r t e s t i n g f o r p r e s s o r a c tiv ity * b u t th i s d ata has not y e t been p u b lish e d . In t h i s t h e s is we a re r e p o rtin g the s y n th e s is of th e 3 - s u b s titu te d th io p h en es co rresp o n d in g to I* II* IH * IV* and VI.

5

C.

S tr u c tu r e and sympathomimetic a c t i v i t y A number of good review s of t h i s f i e l d are a v a ila b le (6 3 -7 0 ),

b u t i t must be borne i n mind t h a t th e se a re now c o n s id e ra b ly o u t- o f d a te , because of the tremendous amount of work th a t has been p u b lish ed w ith in th e p a s t few y e a r s . In 1894, O liv e r and S h a e fe r (71) dem onstrated th a t e x tr a c ts of th e a d re n a l m edulla, on in tra v e n o u s in je c tio n i n t o an im als, produced a marked r i s e in blood p r e s s u re .

Abel (72) f i r s t se p a ra te d th e a c tiv e

hormone as a polybenzoyl d e r iv a tiv e , which was hydrolyzed to a v ery a c tiv e m a te r ia l.

I t was some y e a rs l a t e r b efo re the tru e e m p iric a l

form ula, CgH-^NO^ was deduced (7 3 ,7 4 ), and i n 1904, e p in ep h rin e ( I ) was sy n th e siz e d by S to lz (7 5 ,7 6 ).

X Curious ab o u t a r e p o rt of th e p r e s s o r e f f e c t of e x tr a c ts of p u tr id meat (7 7 ), B arger, Dale and coworkers re p eated th e work, is o la te d and i d e n t i f i e d (7 8 ,7 9 ) th e a c tiv e a g e n ts:

isoamylamine ( I I ) ,

phenyle thylam ine ( H i ) , and tyram ine (IV ).

- C H

0 Hz a Hz A re a ]

M il

>

X

33

S m ith (167) f o r th e p re p a ra tio n of benzylam ine from p h e n y la c e ty l c h lo r id e . y # -(5 -T h ie n y l)-p ro p io n ic a c id ( I I ) was co n v erted to th e a c id c h lo rid e (IV) by means of th io n y l c h lo r id e .

This a c id c h lo r id e , in an i n e r t s o lv e n t such

as benzene, i s re flu x e d w ith sodium a z id e ; the/< ?-( 3- th ie n y l) - p r o p io n y l a z id e form ed re a rra n g e s a t th e tem p eratu re of th e r e a c tio n m ixture to / 3 - ( 3 - t h i e n y l ) - e t h y l is o c y a n a te , w hich, w ith o u t i s o l a t i o n , was hydrolyzed w ith h y d ro c h lo ric a c id to th e amine, I .

The a c id c h lo rid e r e a c ts v i o le n t ly ,

alm o st e x p lo s iv e ly , w ith sodium a z id e a t room te m p e ra tu re , u n le ss i t i s f i r s t d ilu te d w ith an i n e r t s o lv e n t such a s benzene. F ollow ing th e d ir e c tio n s given by W o rra ll (168) f o r th e p re p a ra tio n of a > -n itro s ty re n e , 5 -thenaldehyde was condensed w ith n itro m e th a n e , u sin g sodium hydroxide as th e c a t a l y s t , producing O J -n itro -5 -v in y lthiophene (V ). B arg er and Easson ( 8 ) re p o rte d th e p re p a ra tio n of th e 2 - t h i e n y l an alo g , b u t gave n e i t h e r d ir e c tio n s n o r a n a ly s is .

Subsequent to th e com pletion

cIH~ C.HHO. 5 X I o f t h i s work, King and Nord (169) a ls o re p o rte d th e 2 - th ie n y l an alo g , p re p ared by a s im i l a r m ethod.

- N itr o - 3 - v in y l thiophene was reduced to

/ 3 - ( 3-th ie n y l) - e th y la m in e u sin g lith iu m aluminum h y d rid e , acco rd in g to th e p ro ced u re d e s c rib e d h e re in under th e p re p a ra tio n of l- p h e n y l- 2 -p ro p y lam in e. /3 -(3 -T h ie n y l)-e th y la m in e was a ls o p rep ared by th e re d u c tio n of 3- t h i e n y l a c e t o n i t r i l e (VI) w ith lith iu m aluminum h y d rid e , acco rd in g to

th e g e n e ra l procedure d e sc rib e d by Nystrom and Brown (163) f o r s im i la r n itrile s .

The amine p re p ared by t h i s method m ight be expected to c o n ta in

.5

s JZX

a tr a c e of N-methy1 - 5 - th en y lam in e, w hich m ight be formed by re d u c tio n of 3 -th e n y l iso c y a n id e ( V II), a sm all amount of w hich would be expected to be p r e s e n t in th e n i t r i l e , V I.

The ^ - ( 3 -th ie n y l)-e th y la m in e p rep ared by

O u rtiu s d e g ra d a tio n of /2 -( 3 - th ie n y l) - p r o p io n ic a c id o r by re d u c tio n of £ d - n itro -3 -v in y lth io p h e n e , however, would be expected to be p u re . /3 -(3 -T h ie n y l)-e th y la m in e h as been converted to th e h y d ro c h lo rid e * by p a s sin g a strea m of d ry hydrogen c h lo rid e i n to an a b s o lu te a lc o h o l s o lu tio n o f th e am ine.

F o r i d e n t i f i c a t i o n p u rp o ses, the benzoyl ( la )

and p h e n y lth io u re a ( lb ) d e r iv a tiv e s of th e amine have been p re p a re d .

The f i r s t method used f o r th e p re p a ra tio n of N-methyl 7