3-substituted thiophenes

95 Pages·03.733 MB·English

by  Mccarthy, Walter C

3-SUBS TITUTSD THIOPHENES
BY
w alter c. McCarthy
Submitted to the Paculty of the Graduate School
in partial fulfillm ent of the requirements
for the degree, Doctor of Philosophy,
in the Department of Chemistry,
Indiana University,
August, 1949
ProQuest Number: 10296521
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ACKNOWLEDGEMENT
The author wishes to express his sincere appreci­
ation to Professor E. Campaigne for his guidance
and encouragement during the course of this in­
vestigation.
This opportunity is taken to express the author!s
indebtedness to the Sterling-Winthrop Research
Institute for the fellowship for the years 1948
and 1949.
To my wife, Mary, this thesis is dedicated.
TABLE OF CONTENTS
INTRODUCTION.......................................................................................................................... 1
HISTORICAL.............................................................................................................................. 2
A. Mono-3-substituted thiophenes.......................................................................... 2
B. Thiophenes as sympathomimetics...................................................................... 3
C. Structure and sympathomimetic a c tiv ity ..................................................... 5
D. Structure and penicillin production stimulant activity .................. 15
E. Structure and anticonvulsant activity..............................................................17
F. Methods of preparation of amines previously used for
thiophene compounds....................................................................................................19
DISCUSSION..................................................................................................................................23
A. Bromination of 5-methylthiophene.......................................................................23
B. Preparation of previously known compounds....................................................27
C. Preparation of new compounds.................................................................................32
EXPERIMENTAL..............................................................................................................................40
A. Bromination of 3-methyl thiophene .........................................................40
1. Study of peroxide catalysts.........................................................................40
2. Attempted reaction with N-bromophthalimide.......................................42
3. Phosphorus pentachloride as halogenating agent ............................ 43
4. Preparation of 3-thenyl bromide.................................................................43
5. Attempted reaction of 2-bromo-5-methylthiophene with
hexamlne.................................................................................................................43
B. Preparation of previously known...compounds.....................................................45
1. Succinimide............................................................................................................45
2. N-Bromosuccinimide...........................................................................................46
3. Benzoyl peroxide...............................................................................................46
4. Cobalt naphthenate ....................................................................................... 46
ii
5. N-Bromophthalimide.............................................................................................47
6. Hydrazoic a c id .....................................................................................................47
7. l-Phenyl-2-nitropropene....................................................................................48
8. l-Phenyl-2-aminopropane....................................................................................48
9. 3-Thenaldehyde.....................................................................................................49
10. 3-^henoic a c id .....................................................................................................50
11. 3-Thienylacetonitrile.........................................................................................51
12. 3-Thienylacetic a c id .........................................................................................51
C. Preparation of new compounds...............................................................................52
1. Diethyl 3-thenylmalonate ........................................................................... 52
2. 3-ThenylmaIonic a c id ............................................ 52
3. ^-(5-Thienyl)-propionic a c id ......................................................................53
4. /^-(3-Thienyl)-propionyl chloride.............................................................53
5. itf-Nitro-3-vinylthiophene...............................................................................53
6. ft - (3-Ihienyl) -e thylam ine...............................................................................54
a. Attempted Dchmidt degradation............................................................54
b. Curtius degradation................................. 55
c. Reduction of co-nitro-3-vinylthiophene ...................................... 55
d. Reduction of 3-thienylacetonitrile....................................................56
e. Hydrochloride...............................................................................................57
f. Benzoyl derivative.......................................................................................57
g. Phenyl thiourea derivative.....................................................................57
7. N-Benzal-^-(3-thienyl)-ethylamine ........................................................ 58
8. 3-%ienylacetyl chloride...................................................................................58
9. N-Methyl-3-thienylacetamide....................................................... 58
iii
N-Methyl-y$-( 3-thienyl) -e thylamine........................................................ 59
a. Methylation of the Schiff base . . . . . . . . . . . . . 59
b. Reduction of IL-methyl-3-thienylacetamide............................... 59
c. Phenylthiourea derivative................................................................. 60
l-(3-Thienyl)-2-nitropropene ................................................................. 60
3-1hienylacetone ........................................................................................... 61
a. Preparation.............................................................................................. 61
b. 2,4-Pinitrophenylhydrazone............................................................. 61
c. Oxime........................................................................................................... 62
l-( 3-Thienyl)-2-aminopropane................................................................. 62
a. Leuckart reaction.................................................................................. 62
b. Reduction of l-(3-thienyl)-2-nitropropene............................... 63
c. Benzoyl derivative .............................................................................. 64
d. Phenylthiourea derivative................................................................. 64
1-(3-Thienyl)-2-methylaminopropane 65
a. Leuckart reaction, alkaline hydrolysis ................................... 65
b. Leuckart reaction, acid hydrolysis ........................................... 66
c. Phenylthiourea derivative................................................................. 66
d. Other derivatives.................................................................................. 66
Ethyl 3-thienylacetate .............................................................................. 66
N- (2 ^-Hy d r osy e t hyl) - 3- th i e ny la c e t amid e ........................................... 67
3-Thienylacetylurea...................................................................................... 68
Methyl 3-thenoate........................................................................................... 68
3-Thenhydrazide............................................................................................... 69
N-Dimethyl-3-thenylamine .......................................................................... 69
3-Thenyl alcohol ........................................................................................... 70
iv
22. 1-(3-Thienyl)-ethanol.........................................................................................70
23. l-( 3-Thienyl )-propanol....................................................................................71
24. 2-(3-Thenyl)-imidazoline ........................................................................... 72
25. 3-Thenyltrimethylaimoninm bromide...............................................................72
SUMMARY...........................................................................................................................................73
BIBLIOGRAPHY..............................................................................................................................74
VITA................................................................................................................................................62
v
INTRODUCTION
1
INTRODUCTION
This thesis represents part of a long range research program
under the direction of Professor E. Campaigne, involving the preparation
of analogues of physiologically active compounds containing the 3-
substituted thiophene ring, and comparison of the activities thereof,
with those of the corresponding 2-substituted thiphenes, and vhLth those
of the benzene analogues (1-4).
Many cases have been studied in which a benzene ring of a physio­
logically active compound has been replaced by a 2-substituted thiophene
ring. This literature has been thoroughly reviewed by LeSuer (5).
Generally the physiological activity remained of the same order of
magnitude, but sometimes increased activity, or decreased activity, was
reported. All of this previous 7*ork has involved 2-substituted thiophenes;
preparation of the 3-substituted ones involved procedures too long and
laborious to be of interest. However, the work of Campaigne and LeSuer (l)
has made 3-substituted thiphenes more readily available.
Sympathomimetic drugs 7jere selected for this investigation because
of the remarkable success that has been attained in correlating physio­
logical activity with structure, and because of the wide variety of
compounds that have been investigated previously in this field.
HISTORICAL