Studies on Mercaptals and Mercaptoles and the Synthesis of Substituted Glutaconimides

73 Pages·4.165 MB·English

by  Brinker, Keith C

PART A
STUDIES OR KERCAPTALS AHD KERCAPT0LE8
AND
PART 1
TIE SYNTHESIS OF SUBSTITUTED GtUTACONIMIDES
Keith Cr Brinfcer
A d issertatio n submitted in p a rtia l fulfillm ent of the require­
ments for the degree of Doctor of Philosophy
in the Department of Chemistry in the
Graduate College of the State
U niversity of Iowa
June, 1951
ProQuest Number: 10666188
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The author wishes to express his alsoere
appreciation to Sr. R. I>. Shriner for his helpful
adrice end guidance during this researOh. Thanks ift
also due to Eli Lilly and Coq>any for their generous
support of the researdh fellowship under which this
work was carried out.
TABLE OF CONTENTS
PART A
Pag®
INTRODUCTION . 1
HISTORICAL .................................... 3
DISCUSSION . . . . . . . . . . . . . ................................. . . .11
EXPERIMENTAL ........................................................ . . . . . . . . . .21
8-Pbenyl-4-bydroxyfflethyl-l,3-dltbi0lane . . . . . . .31
3 ,8-Dimethy1-4-hydroxymetby1-1,3-di th i olane . . . . .21
3,8~D3JBethyl~4~bena0xymethyl~lf3<*&ithiolane . . . . .33
3*3-Bimetbyl-4-p-nit;r0b©nzoxyiB@thyl-l#3-dithiolane, .33
BrPbenyl-A-benaoxymetbyl-l,3~dithiolan© . . . . . . .33
8~Ph©nyl-4-p**nitrobeni&©xyiSietbyl~l#3-dithiolaiie. . . . 33
S,8~Blm©tbyX-4-m©ro&pt0methyl~l,3-©x&tbiol&ne . . . .33
3f 3-Dime$b3rl-4-p~&minobenz0xyfflethyl-l#3-difcbielane. ,34
3,3-DimetbyI~4~p~benzene8ul£Gn&aiidob0nz©xymethyl-l,
3-dithiolane . . . . . . . . . . . . . . . . .35
Preparation of th© 3#4~dinitx<^b©nylthioetb©r of
3, 8-diiaethyl-4-i&ero&ptQiii©tbyl-l, 3-oxathiQlane .25
Preparation of to® p-niixobenzoylthioiester of 3,3-
dimethyl-4-ja©roaptom©tbyl-l,3-oxathiolane . . .36
2 ,2 ,4-Trimethy 1-1,3-oxathiolane . .37
SUMMARY ...................... 38
PART B
INTRODUCTION.............................................................. 89
HISTORICAL .......................................... .31
Glutaconimldee . . . . . . . . . . . . . . . . . . .38
N-Arylglutaconimidea . . . . . . . . . . .41
N-Aikylglutaoonlmidee ............................................43
DISCUSSION . .46
iii
Page
EXPERIMENTAL 53
N-Methyl- * -cyaao- p -m ethylglut& oonim ide..................53
N-Etfcyl-* cK ~oyano- p -methylglut&conimide.....................#53
N-n-Amyl- <* -oyano- <3 -raethylglutaeonXffiide • . . , .54
N-M©thyl*> * ^oyaao- ^ , y -dimethylglut&eonimide , ,55
S-Methyl- oc ~oyano^ £ -methyl- Y -benzyl-
glutaoonimid© , . *56
N-( -Hydroxyethyl)- <x -oyano-^ -methyl-
glut aeon Amide.................................................... . . . *57
The React ion of N-Methyl- <x -cyano- <3 -methy1-
glutaoonimide with Hydro bromic Acid , * . . ,59
The Reaction of N-Methyl- c< -oyano- -methyl-
benzylglutaconimide with Ry&robromic Acid • ,59
N-Methyl- P t v -dimetbylglut&coniiaide . . . . . . .60
N-( $ -bromoethyl)- p -methylglutaoonimide . , • . ,80
The Reaction of N-Methyl- <x -oyano- p -methyl-
glutaconimide with Methyl Iodide . . . . . . .61
The Reaction of Benzyl Bye®id© with N-Methyl-<* -
oyano- 0 -methylglutaoonimide . .....................#63
The Reaction of Methyl Iodide with N-Methyl- p -
me thy Xg1 utacon im id® . . . . . . . . . . . . ,63
SUMMARY , # . . ...................................... .64
BIBLIOGRAPHY ♦ . .................... . . . . . * , .65
BIOGRAPHY ...................................... , . . • .68
i r
1
FAIT A
STUDIES m MERCAPTALS AHD MERCAPT0LIS
m m m nm tm
In view of the faot that adm inistration of 3,3-
diaercaptopropanoX prevents the development of alloxan
diabetes in rate, it was of great interest to study the
possible condensation products of these two compounds,
and to have them tested for diabetogenic activity, Budde
(X) in earlier work had treated alloxan with 3,3-
dimercaptoprop&noi in an attempt to prepare the following
mercaptole*
S— CHCHtOH
The reaction products were polymeric in nature
and indicated that the reaction had probably been com­
plicated by oxidation-reduotion reactions. It was also
suggested that the hydroxyl group of 3,5-dimeroaptopropanol
had entered into the reaction. Consequently it wa® decided
to study the reaction of the dithiol with simple aldehyde®
and ketones. These products wore then to be tested for
physiological activity. Means of synthesizing the above
mentioned meroaptole by indirect method® were also con­
sidered.
3
HISTORICAL
At the onset of World far II a reee&rch program
war laU iated In Ragland to develop antidotes for vesicants*
Stoefcen and Thompson (3) found that when Lewisite was
allowed to reaot with a protein of high thiol content
under physiological oonditions the resulting compound
contained arsenic in combination with two thiol groups#
This observation led them to believe that the toxicity of
Lewisite and other tviv& lm t arsenical© was due to th eir
ab ility to combine with the essential <*SH groups in
certain tissue proteins to form stable areenio-oontaining
rings* These same authors also reasoned that compounds
of type A would be expected t© be more stable than compounds
of type B# Hence simple ditM oIs might form relatively
- c - s ^ c " s \
I As— As —
_ C - s ' - C - 5 ^
/ ^
A B
stable ring compounds with Lewisite and so compete
successfully with *&ithiol* protein® in animal tissue®*
S to len and Thompson then undertook; the synthesis of
a series of 1#& and l#3-dithiol compound® which eventually
3
led to the preparation of the new oonpound, 3,3-dineroapto-
propanol. Thie oowpound, B ritleh Anti-hewielte (oosmonly
ealled BAL)f proved to he highly offootire la stepping
and even reversing the toxio effoots of Lewisite.
C C. Hr s
c h s h + a ''A% CH-CHa — »- i Hs ' AsC“ ~ CHCI
I Cl I
CHzOH CHtOH
BAL is at present being tasted a© a detoxifying agent in
the clinical m e of therapeutic arsenical drugse
Subsequent to the discovery of Ml* hy the B ritish#
methods of preparation of Bal were studied in the United
States so that a presses wOuid he available for large
scale manufacture- A modification of the B ritish process
was developed involving the bromination of ally l alcohol
to glycerol dibromehyarin followed by reaction in an auto­
clave with sodium hydrosulfide to yield SAL (3)-
CH*OH C H*OH C HiOH
( 1 AkSH *
04 CHB* CHSH
q /4 C H^Sh CHZSH
3m
Much of the research on BAI* carried out during
the war years has not appeared in the literature*
lithiolane is the five membered cyclic compound
4
containing two heterocyclic sulfur atoms* Dithiane is
the corresponding six memfcered ring. The nomenclature
for the compounds in whloh m oxygen atom has replaced
a sulfur atom is analogous and is as follows.
4 i
SC^ S K ,
?Wi_SvC/4
1 0 4 CHt
4 CHtrS'
3
> « ,- S,
/, 3-PITHto LANE /,3-DtTH/ANE
6 /
CHt-0 s a CAk-O
/ \ t
I sCHi
J CAi CAk
CM-S
4 \ z'
3 . CM.-S
4 3
1,3-OXATHtOLANE
OXATHiANE
Stocken (4) treated BAX* with benzaldehyd® in a
hensene solution containlag a few drops of hydrochloric acid
and obtained 3~pheayl~4~hydr0xymethyl~l,3~&ithiolane (»,p* ?f°)
in yields of 94$* In a sim ilar maimer Stockea prepared
CAk^ Hd CAk-Sv.
Lush * c4Ar cA<? ». ^
CA*0A CAiO/V
the following compounds hy treating BAI* respectItaly with
a, cet aldehyde, acetone and oyolohsxanone*
3-a»thyl-4-fcydroxyne thyl-i,3»d ith iolase
*,p ., 57-58®; yield, 85#,
3,3-dlnetl^l-4-fcydroxyaethyl-l,3-dith iolane
«,p ., 54-55®; yield, 65#,
3-hydroxynethyl-l,4-dithiaapiro (4.5) deoane
sup., TO®; yield, 65#.
k ,S-C
F 's-ctfi
Bensnldebyde and 1,3-di»eroaptoprop&nol were
also condensed to yield nearly theoretical quant it lea of
3-phenyl-5-hydroxy-l,3-dithiaae melting at 148-143°.
Cfi.SU CUt-S^CtUj-
CHOH + CtUs CHO s ''H
CUtSU
Sjeberg (5) baa studied the following reaotion and
reports the isolation of tooth products. On standing, either
CHtSJZ CHz.SH CHi-S^^CMj
C.HOH + -O k
,Ct/j -f CH-o'
CHtOH 'C“3 7S%
CHfO' ^C/Zj cH*.OH
s
product reverts m equilibrium mixture coneiting of about