The synthesis of 4- substituted thianaphthenes

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Content THE SYNTHESIS OF 4- SUBSTITUTED THIANAPHTHENES
A Thesis
Presented to
the Faculty of the Department of Chemistry
The University of Southern California
In Partial Fulfillment
of the Requirements for the Degree
Master of Science in Chemistry
by
David M. Frisch
December 1950
UMI Number: EP41586
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& e si ?c in
This thesis, written by
tlto ( _ W )
under the guidance of luf&dJFacuity Committee,
and approved by all its members, has been
presented to and accepted by the Council on
Graduate Study and Research in partial fu lfill
ment of the requirements for the degree of
HARRY J. DEUEL, ^r.
TTean
Faculty Committee
Chairman
TABLE OF CONTENTS
CHAPTER
I. INTRODUCTION . . ..............................
II. DISCUSSION OF RESULTS .......................
Synthesis of 4-keto-4*5,6,7-tetrahydrothia-
naphthene ................................
Grignard reaction.................... . . .
Reformatsky reaction .....................
Leuckart reaction .........................
Schroeter reaction .......................
Horning reaction .........................
Cyanohydrin reaction .....................
III. EXPERIMENTAL.......... .......................
Attempt to cyclicize Y-(2-thienyl)-n-
butyric acid using hydrogen fluoride . .
Reaction of 4-keto-4,5*6*7-tetrahydrothia-
naphthene with Grignard reagents ....
Reformatsky reaction of 4-keto-4*5,6*7-
tetrahydrothianaphthene with ethyl
bromacetate ..............................
Leuckart reaction with 4-keto-4*5*6*7-
tetrahydrothianaphthene .................
Attempt to prepare 4-aminothianaphthene
from the oxime of 4-keto-4,5*6*7-tetra-
hydrothianaphthene (XX) .................
iii
CHAPTER PAGE
Attempt to prepare 4-aminothianaphthene
from 4-keto-4,5,6,7-tetrahydrothia-
naphthene azine (XXII) ................. 20
Attempt to prepare 4-hydroxy-4-carboxy-4,
5,6,7-tetrahydrothianaphthene 21
IV. SUMMARY...................................... 23
BIBLIOGRAPHY........................................ 24
ACKNOWLEDGMENT
The author is indebted to Dr. M. C. Kloetzel for
his long and patient guidance in this investigation.
CHAPTER I
INTRODUCTION
Although many substituted thianaphthenes have been
prepared, only two 4-substituted compounds, 4-hydroxythia-
naphthene (l) and 4-aminothianaphthene (2) have thus far j
been reported. With the synthesis of 4-keto-4,5>6,7-tetra- (
hydrothianaphthene (IV) by Fieser and Kennelly (l) easy j
access to the 4-position through the reactive carbonyl group:
is afforded. The work herein reported was undertaken with t
;the object of preparing a number of 4-substituted thianaph- 1
<
thenes which might possess some properties of biological
interest. For example, 5-aminothianaphthene has shown tuberi
i
culostatic activity (3) and it was thought that the testing
.of the 4-amino compound might prove to be of interest. Also!
4-thianaphthenylacetic acid might be comparable to indole-3-
acetic acid as a plant growth hormone. j
I
The reactions undertaken with 4-keto-4,5,6,7-tetra-
i
hydrothianaphthene were Grignard additions to prepare the ,
4-methyl and 4-phenyl derivatives, the Reformatsky reaction :
to prepare 4-thianaphthenylacetic acid, and finally the :
.Leuckart, Horning, and Schroeter reactions in attempts to 1
prepare 4-aminothianpahthene by a simpler method than that 1
reported by Fries (2). >
CHAPTER II
DISCUSSION OF RESULTS
Synthesis of 4-keto-4,5*6,7-tetrahydrothlanaphthene. >
The preparation of 4-keto-4,5,6,7-tetrahydrothianaphthene
(IV) was accomplished by the method of Fieser and Kennelly
U).
O + qSSt* i
C-O ^
O
o i ,
W £ n r . ) cm
The yields in the four reactions of the sequence were
:70, 50, 93> and 49 per cent, respectively, as compared with
54, 72, 90, and 90 per cent reported by Fieser and Kennelly.
Attempts to increase the yield of II by the application of
,the Martin modification (4) of the Clemmensen reduction fail
ed. Likewise, attempts to use anhydrous hydrogen fluoride
(5) for the direct cyclization of II only resulted In the
recovery of?f-(2-thienyl)-n-butric acid. ;
1
, Grignard reaction. The reaction of 4-keto-4,5,6,7-
tetrahydrothlanaphthene (IV) with Grignard reagents proceed-:
ed smoothly. The two hydroxy intermediates, 4-hydroxy-4- !
!
methyl-4,5,6,7-tetrahydrothianaphthene (V) and 4-hydroxy-4-
phenyl-4,5^6,7-tetrahydrothianaphthene (VI) were unstable i
3
and decomposed within one to three weeks on standing at room
temperature. Dehydration and dehydrogenation of the carbinols
with sulfur (6) produced 4-raethylthianaphthene (VII) and 4-
phenylthianaphthene (VIII) in yields of 8l and 80 per cent re
spectively. Conversion of 4-phenylthianaphthene to the sulfone
(12) (IX) in 79 per cent yield was effected by hydrogen peroxide.
-ir* JJj
0
Reformatsky reaction. In the Reformatsky reaction (15)
of 4-keto-4,5,6,7-tetrahydrothianaphthene (IV) with ethyl bro-
moacetate, the isolated material was not the hydroxy ester but
a mixture of unsaturated esters (X, XI). This loss of water has
been frequently reported in Reformatsky type reactions (15)*
1 J»*rcVM6r
I -
(20
<30 ,gO + < qO
cH*r CH-c©^
I7O tpC* ^ Cm)
1 ^
L ftce
g Q m
4
No attempts were made to separate the two esters; but upon
saponification, followed by acidification, two acids, m.p.
186° -187° and 107° -109° respectively, were obtained.
1
Both showed the correct analysis for the composition C-^qH^q
O2S. Separation was effected by virtue of the greater
solubility of the lower melting compound in acetic acid.
Ozonolysis of the two isomeric acids would be expected to
proceed in the following manner.
However, ozonolysis of the higher melting compound yielded
no identifiable products. One of the potential ozonolysis
products is 4-keto-4,5,6,7-tetrahydrothianaphthene (IV), but
no trace of this compound or its oxime (XX) was found. The
lower melting compound was not obtained in quantity adequate
for ozonolysis studies.
Dehydrogenation (9) and subsequent saponification of
the mixture of esters (X) and (XI) obtained from the Re
formatsky reaction yielded only one compound, 4-thianaph
thenylacetic acid (XIV) which was easily converted to the
sulfone (12) (XV).
5
Leuckart reaction. The first attempts to apply the
Leuckart reaction (10) to the preparation of 4-amino-4,5>6,
7-tetrahydrothianaphthene (XVI) were unsuccessful because of
hydrolysis of the intermediate N-formyl-4-amino-4,5*6,7-
tetrahydrothlanaphthene (XVI) with the recommended (10) con
centrated hydrochloric acid resulted in resinification. How
ever, by using a 10 per cent hydrochloric acid solution (ll)
and heating below the boiling point, hydrolysis was effect- '
ed with practically no resinification, and 4-amino-4,5,6,7-
tetrahydrothianaphthene (XVII) was obtained in 52 per cent
S(XSQ a £KZC)
The amine was easily converted to its acetyl (XVIII)
and benzoyl (XIX) derivatives in the customary manner (7>
13)* When 4-acetamido-4,5>6,7-tetrahydrothianaphthene was
subjected to dehydrogenation conditions, using chloranil
(9> 14), sulfur (6), or palladium on carbon (8) catalyst, no
dehydrogenation products could be isolated. With the
chloranil the only materials recovered were a small amount
of XVII plus a large amount of tetrachlorohydroquinone. The
sulfur dehydrogenations yielded brown tars. The results
6
indicate that more than mere dehydrogenation occurred. With
the palladium-carbon catalyst the starting material (IV) was
recovered unchanged.
Schroeter reaction. Schroeter (l6) was able to con
vert the oxime of 1-tetralone into 1-aminonaphthalene in one
i
step in yields of 50 per cent by the passage of anhydrous !
i
hydrogen chloride into a solution at 50°, which contained !
the oxime of 1-tetralone, acetic anhydridride, and glacial
acetic acid. Similar treatment of the oxime (17) of 4-keto-.
4,5,6,7-tetrahydrothianaphthene (XX) failed to produce any
of the desired 4-aminothianaphthene. Varying the temperature
between 0°uand 80° also failed to effect conversion to the
amine. However, when dry benzene and acetic anhydride were
employed instead of glacial acetic acid, the acetate of the J
oxime (XXI) was isolated in 67 per cent yield
When XXI was heated with 2N sodium hydroxide (18), and the |
solution then acidified with solid carbon dioxide, the
oxime was obtained. This proved that acetylation had occur-;
red at the hydrogen of the hydroximino group.
Horning reaction. In an attempt to prepare 4-amino-
thianaphthene by the Horning reaction (19), the azine (XXII)
of IV was prepared in good yield. However, when refluxed
with 5 per cent palladium on carbon catalyst, suspended in
diphenyl ether or mineral oil, the azine was not converted
to the expected amine.
Failure of the palladium-carbon catalyst to cause cleavage
of the azine and dehydrogenation of the resulting fragments
to the desired amine may possibly be attributed to the
poisoning of the catalyst by the sulfur.
cyanohydrin of IV with hydrogen cyanide (20) was unsuccess
ful . The adverse effect of the strongly acidic hydrolytic
mixture on the thiophene nucleus seemed to be the principal
cause of the failure in this instance.
O
< IZ )
Cyanohydrin reaction. Attempts to prepare the
CHAPTER III
EXPERIMENTAL*
Attempt to cyclicize T-(2-thienyl)-n-butyrlc acid
using hydrogen fluoride (5).— Anhydrous hydrogen fluoride
(200 g.) and ^-(2-thienyl)-n-butyrie acid (II, 12 g.) were
mixed in a copper vessel and allowed to stand at room tem
perature for two hours. After this period the mixture was !
i
poured into ice water and then extracted with ether. When
shaken with a 10 per cent sodium carbonate solution, the
extracted material passed completely from the ether to the
water layer, indicating that no cyclization had taken place.
Acidification of the water layer yielded 9*8 g. of T ‘ -(2-
thienyl)-n-butyric acid.
Reaction of 4-keto-4,5,6,7-tetrahydrothianaphthene
■ with Grignard reagents.— (a) Preparation of 4-hydroxy-4-
methyl-4,5,6,7-tetrahydrothianaphthene (V). To the Grignard
reagent prepared from 4.5 g* (*025 mole) of methyl iodide, '
1
35 cc. of anhydrous ether and 0.8 g. (.03 mole) of magnesium,
a solution of 3*5 g. (.023 mole) of 4-keto-4,5*6,7-tetra
hydrothianaphthene (IV) In 25 cc. of anhydrous ether was
.added dropwise at room temperature over a period of two hours.
♦Analysis of compounds V— VII by the author; VIII—
;XIV, XVI— XX and XXII by Adalbert Elek of the. Elek Micro-
analytical Laboratory, Los Angeles, California; and XXI j
by J. Pirie, University of-Southern. California. - --- — --
9 .
A white complex formed immediately. When the addition was
completed, the mixture was chilled and 9 cc. of a saturated
ammonium chloride solution was added to hydrolyze the com- ,
■ plex. The basic magnesium salt sank to the bottom of the
vessel and the ethereal layer was decanted and evaporated
to drynessj yield 7.0 g. (89$) of 4-hydroxy-4-methyl-4,5,6, ,
7-tetrahydrothianaphthene (V). Repeated recrystallizations
with Skellysolve "B" gave colorless cubic crystals, m.p. 1
75° -77°• Decomposition to a brown mass occurred on stand
ing at room temperature for two weeks.
*
Anal. Calc'd. for C9H12OS: S, 19>06$. Found: S,
18.46$.
(b) Preparation of 4-methylthianaphthene (VII) (6).
A mixture containing 3*8 g. (.023 mole) of 4-hydroxy-4-
methyl-4,5>6,7-tetrahydrothianaphthene (V) and 0.72 g.
(.0 2 3 mole) of powdered sulfur was placed in an eight inch
!test tube. On heating to 150° a large amount of water vapor
was evolved. When the vapor was completely removed the
t
temperature was elevated to 230° for twenty minutes, then
to 250° for an additional ten minutes to complete the re
action. During this time a large quantity of hydrogen
!sulfide was eliminated. Vacuum distillation of the residue ;
; .
at 62° -64° / 2 mm. gave 2 .7 g. (81$) of the colorless, li- j
quid, 4-methylthianaphthene (VII); m.p. -6° to -4°. |
Anal. Calc'd. for C^HqS: S, 21.63$. Found: S,
2 1. 60$.
(c) Preparation of 4-hydroxy-4-phenyl-4>3j6 ,7-tetra
hydrothianaphthene (VI). To the Grignard reagent prepared
from 8 .0 g. ( .0 5 mole) of bromobenzene, 50 cc. of anhydrous
ether, 1 .5 g. ( .0 6 mole) of magnesium, with a crystal of
iodine as a catalyst, was added a solution of 4.0 g. (.0 2 6
mole) of 4-keto-4,5>6,7-tetrahydrothianaphthene (IV) in 25
cc. of anhydrous ether. This was added dropwise to the re
agent over a period of two hours. Stirring was continued
for an additional three hours after which hydrolysis of the
complex was effected by the addition of 10 cc. of a saturat
ed ammonium chloride solution. The ethereal solution was
decanted and evaporated to dryness under aspirator pressure
yield 5 .0 g. (80$) of solid 4-hydroxy-4-pehny1-4,5,6,7-
tetrahydrothianaphthene (VI). Repeated recrystallizations
with Skellysolve "F" gave colorless needles, m.p. 65° -67°.
Decomposition to a brown tar occurred on standing at room
temperature for one week.
Anal. Calc'd. for C-j^H-^OS: S, 1 3. 92$. Found: S,
13.50$.
(d) Preparation of 4-phenylthianaphthene (VIII) (6).
A mixture containing 4.0 g. (.018 mole) 4-hydroxy-4-phenyl-
11
4,5*6,7-tetrahydrothianaphthene (VI) and 0.55 g- (*018 mole)
of sulfur was placed In an eight inch test tube and heated
in a manner previously described. Vacuum distillation of
the product at 134° /3mm. yielded 2.8 g. (80$) of 4-phenyl-
thianaphthene (VIII). Recrystallization from 95$ ethyl al- ,
cohol gave white crystals, m.p. 46° -47°. ;
Anal. Calc’d. for C^H^S: C, 79-95$; H, 4.79$- !
Found: C, 79-24$; H, 4.67$.
A mixture containing 0.5 g- (.0024 mole) of 4-phenyl-'
thianaphthene (VIII), 3 cc. of glacial acetic acid and 2.5
cc. (-0 2 5 mole) of 30$ hydrogen peroxide was refluxed for
one hour, during which time the 4-phenylthianaphthene went
into solution very slowly. After the one hour period, 10
cc. of water was added and the mixture was allowed to cool
in the refrigerator. This resulted in the crystallization
of 0.46 g. (79$) of 4-phenylthianaphthene-l-dioxide (IX)
(12). Recrystallization from an alcohol-water solution
yielded white needles, m.p. 139°-
Anal. Calc’d. for C-^H^OgS: C, 69-42$; H, 4.12$.
Found: C, 69-27$; H, 4.32$. :
Reformatsky reaction of 4-keto-4,5*6,7-tetrahydro
thianaphthene with ethyl bromacetate (15)-— (a) Preparation
of unsaturated esters._X and XI. A. hot mixture, of—48_g . _of_. .
clean, dry zinc amalgam, 0.4 g. of iodine and 12 cc. of
ethyl bromoacetate in 200 cc. of dry benzene and 200 cc. of .
dry ether was prepared. To this mixture was added 16 g. of
4-keto-4,5,6,7-tetrahydrothianaphthene (IV). After the
i
iodine color had disappeared the solution became yellow-
orange in color. Forty-eight grams of zinc amalgam and 0.4 '
g. of iodine were added every half hour for two hours, after
r
which 12 cc. of ethyl bromoacetate was again added and the
mixture refluxed for an additional two and one half hours.
After the refluxing period the mixture was cooled and the
condensation product decomposed with cold 10 per cent hydro
chloric acid. The benzene-ether layer was separated and the
water layer extracted twice with benzene. The combined
extracts were washed first with dilute ammonium hydroxide,
then with water, and finally distilled at 135° -130° /3mm.;
yield 17 g. (68$) of mixed unsaturated esters (X) and (XI).
Anal. Cale’d. for Ci2Hi4°2S: C, 64.86$j H, 6-30$.
Found: C, 64.60$; H, 6.46$. 1
(b) Hydrolysis of the esters. Two grams of the
aforementioned ester mixture was heated with 50 cc. of 20$
sodium hydroxide solution until the organic layer disappear
ed. The mixture was neutralized with concentrated hydro
chloric acid and the solid precipitated acids extracted witli
ether . -The ether was evaporated-and-the residuaT-solid-was 1
13 ;
recrystallized from glacial acetic acid to yield 1.4 g.
(76$) of colorless crystals, m.p. 186° -l87°«
Anal. Calc’d. for C1ohio°2^: c ’ 61*90$; H, 5.15$.
Found: C, 61.79$; H, 5-22$.
When the acetic acid mother liquor was diluted with
water, 0.2 g. (10$) of the isomeric acid separated into 1
needle-like crystals, m.p. 107° -109°•
Anal. Calc’d. for C10H1002S: C, 6 1. 90$; H, 5-15$.
Found: C, 6l.8l$; H, 5‘35$.
Five tenths gram of the acid melting at 186° -I870
was dissolved in 70 cc. of ethyl acetate and subjected to
ozonolysis for thirty minutes at room temperature. During
this period five liters of 3*5 per cent ozone in oxygen was
passed into the solution. Completion of the reaction was
indicated by the change from colorless to red of a potas
sium iodide test solution placed in the ozonolysis system
so that any unused ozone would pass through the potassium
iodide solution before leaving the system. The solution of
ozonide was then added to 25.cc. of water and allowed to
stand overnight at room temperature. The two layers were
then separated and the water layer was shaken with an equal
volume of ether which was then added to the ethyl acetate
14
layer. The solvents were evaporated leaving a brown oil
which was dissolved in a 10 per cent sodium carbonate solu
tion except for a small quantity of brown solid. This solid
failed to form an oxime. Acidification of the sodium
carbonate solution yielded a brown oil which could not be
identified.
(c) 4-Thianaphthenylacetic acid (XIV) (9)- A solu- 1
tion composed of 12 g. (.054 mole) of the mixture of un
saturated esters obtained from the Reformatsky reaction and
14.5 g. (*0 5 9 mole) of chloranil in 100 cc. of commercial
xylene was refluxed for thirty six hours. The mixture was
then cooled and filtered to remove the tetrachlorohydro-
quinone. The remaining mixture was distilled at 130° /3 mm.'
to yield 6-5 g* (55$) of the dehydrogenated ester. Upon
saponification and subsequent acidification, 4.1 g. (71$)
of 4-thianaphthenylacetic acid (XIV) was obtained. Re-
crystallization from water yielded white needles, m.p.
146° -146.5°.
Anal. Calc 1 d. for C10H802S: C, 6 2. 50$; H, 4.17$.
Pound: C, 62.45$; H, 4-35$.
A mixture containing 0.5 g. ( .0024 mole) of 4-thia
naphthenylacetic acid (XIV), 3 cc. of glacial acetic acid
and 2.5 cc. (.024 mole) of 30 per cent hydrogen peroxide was
1 5 1
refluxed for fifteen minutes and then evaporated to dryness.’
i
Crystallization of the yellow residue from water yielded j
t 0.4 g. (70$) of colorless dioxide (XV) of 4-thianaphthenyl- j
acetic acid, m.p. l8l°.
Anal♦ Calc’d. for C10H804S; 53-57$; H, 3-57$-
Found: C, 53-35$; H, 3-‘
Leuckart reaction with 4-keto-4,5,6,7-tetrahydrothia
naphthene .--( a ) Preparation of 4-amino-4,5,6,7-tetrahydro- !
! i
; thianaphthene (XVII) (10). Formamide (16 g.) was placed inJ
a distilling flask and heated slowly to 165°. At this tem- :
!
perature, 10 g. of 4-ket0-4,5,6,7-tetrahydrothianaphthene j
; (IV) was added and the mixture was heated between 165° -1859
■ until there was no further deposit of ammonium carbonate in !
i
I
the side arm of the flask. This operation required three to
j five hours. The water and ketone which distilled during thijs
\
1
1 period were collected in a separatory funnel and the ketone
i
.was returned to the reacting mixture. After the heating
1 period, the liquid was allowed to cool and twice its volume j
: of water was added. Upon vigorous shaking, N-formyl-4- !
1 I
i l
! amlno-4,5,6,7-tetrahydrothianaphthene (XVI) was obtained as j
a brown solid; yield 9-0 g- (76$). This crude material was
1
then hydrolyzed by gentle heating for four hours with 60 cc.
1 of 10 per cent hydrochloric acid. The light brown liquid
- obtained- was-then-cooled and—10-per-cent-sodium-hydroxide--
16
was added until the mixture was definitely alkaline. A
heavy brown oil separated from the water phase. The oil
was extracted with ether, washed with water and dried over
anhydrous sodium sulfate. Vacuum distillation at 74° -78°
' / 2 mm. gave 5*2 g. (52$ based on amount of ketone used) of
the colorless, liquid, 4-amino-4,5>6,7-tetrahydrothianaph
thene (XVII). .
i
Anal. Calc Id. for C3Hi;lNS: C, 6 2.69$; H, 7-24$.
Pound: C, 6 2. 87$; H, 7-22$.
One gram of 4-amino-4,5,6,7-tetrahydrothianaphthene
(XVII) was gently heated with three times its volume of
acetic anhydride and then poured into 40 cc. of cold water.
The precipitated 4-acetamido-4,5,6,7-tetrahydrothianaphthene
(XVIII) (7) was recrystallized from 20 per cent alcohol to ;
yield 1.02 g. (81$) of white crystals, m.p. 168° -I690.
t
Anal. Calc rd. for C^R^NOS: C, 61.50$; H, 6.71$; ;
S, 16.42$. Found: C, 61.80$; H, 6.79$; S, 16.15$. !
A mixture of 1 cc. of 4-amino-4,5,6,7-tetrahydro-
1
thianaphthene (XVII), 3 cc. of water and 1 cc. of benzoyl
chloride was shaken with 5 cc. of 10 per cent sodium hydro
xide (added in three portions) until a precipitate was ob-
r
tained. Recrystallization of 4-benzamido-4,5>6,7-tetrahydro-
i
-thianaphthene (XIX-)- (13) from alcohol-water gave white . . . J
: 17 ]
I crystals, m.p. 123-5° -124.5°- i
Anal. Calc'd. for C15H15NOS: C, 70.20$; H, 5-'
i
! S, 12.45$; N, 5-40$. Pound: C, 70.22$; H, 6.02$; S, 12.06^;
i
N, 5-54$. |
I
|
(b) Attempt to dehydrogenate 4-acetamldo-4,5,6,7-
tetrahydrothlanaphthene (XVIII) using chloranil (14). Five
i
i tenths of a gram ( .0026 mole) of 4-acetamino-4,5,6,7-tetra-
I
jhydrothianaphthene (XVIII) and 1.26 g. (.0052 mole) of
! chloranil were dissolved in 110 cc. of xylene and refluxed
; for twenty four hours. After cooling, an equal volume of
j i
! ether was added and the organic mixture was shaken with 10 j
i I
! per cent sodium hydroxide. The water layer beoame black and
I I
l was separated from the organic layer. The organic layer of i
1 I
; xylene-ether was then distilled under reduced pressure. The1
| residue was heated with an alcohol-water solution and filter-
\
ied. On cooling, .05 g. of the starting material, 4-acetamido
i
i
I 4,5,6,7-tetrahydrothlanaphthene (XVIII), was recovered.
*
; This represented the only identifiable material recovered
1 in the reaction.
j ( c ) Attempt to dehydrogenate 4-acetamido-4,5,6,7-
I
1tetrahydrothlanaphthene (XVIII) using sulfur (6). A mixture
jof .033 g* (.00102 mole) of sulfur and 0.1 g. ( .00051 mole)
| of 4-acetamido-4,5,6,7-tetrahydrothianaphthene (XVIII) was
Lheat.ed..for_twenty_mInutes-.at_24.0O During~the-heating-period
18
a detectable amount of hydrogen sulfide was given off. How
ever, at the conclusion of the heating only a brown tarry
material remained in the test tube, and when warmed with an
alcohol-water solution and filtered, neither the starting
material (XVIII) nor 4-acetaraidothianaphthene was obtained.
(d) Attempt to dehydrogenate 4-acetamido-4,5*6,7-
tetrahydrothianaphthene (XVIII) using palladium-carbon (8). ;
A mixture of .03 g* of 4-acetamido-4,5,6,7-tetrahydrothia
naphthene (XVIII) and .004 g. of 30 per cent palladium on
carbon catalyst was placed in a test tube so fitted as to
pass any liberated hydrogen gas into a burette where the
amount of water displaced by the gas could be read directly.
The system was flushed with nitrogen and the mixture heated
to 220° -250° for one hour. During this period no hydrogen
was liberated.
Attempt to prepare 4-amlnothianaphthene from the oxime
of 4-keto-4,5,6,7-tetrahydrothianaphthene (XX).— (a) Oxime
of 4-keto-4,5,6,7-tetrahydrothianaphthene (XX) (17)• Two
tenths of a gram of 4-keto-4,5,6,7-tetrahydrothianaphthene
(IV) was added to a solution composed of 0.5 g- of hydro-
xylamine hydrochloride, 3 cc. of water and 2 cc. of 10 per
cent sodium hydroxide. To this mixture absolute alcohol was
added until a clear solution was obtained. After heating
for fifteen minutes on a steam bath and then allowed to cool,
19
0.21 g. (95^) of the oxime (XX) was obtained. Recrystalli
zation from 40 per cent alcohol gave white crystals, m.p.
128° -129°.
Anal. Calc’d. for CsHgNOS: C, 57.48^; H, 5-38$.
Pound: 57-61$; H, 5-31$.
(b) Attempt to convert the oxime (XX) to 4-aminothia
naphthene in glacial acetic acid (16). A solution of 0.5 g.
of the oxime (XX) in 2 cc. of glacial acetic acid and 0.4 cc.
of acetic anhydride was heated to 60° -80° for a period of
two and one half hours. During this time, anhydrous hydrogen
chloride was passed into the solution. Precipitation of the
amine hydrochloride did not occur. When the solution was
evaporated to dryness under aspirator pressure, white cry
stals were obtained which upon recrystallization from alcohol-
water gave a compound which gave no m.p. depression with the
oxime.
(c) Attempt to convert the oxime to the amine in
anhydrous benzene. A solution of-0.5 g. of the oxime, 0.4
cc. of acetic anhydride and 5 cc. of dry benzene was kept
at room temperature (25°) while anhydrous hydrochloric acid
was passed into it for two and one half hours. No precipi
tation occurred during this time. After evaporating to
dryness under aspirator pressure .42 g. (67$) of the acetate
20
of the oxime (XXI) was obtained. Recrystallization from
alcohol-water yielded white needles, m.p. 133° -134°.
Anal. Calc'd. for CiQHuNOgS: C, 57*39$; H, 5*30$.
Found: C, 57*14$; H, 5*23$*
A mixture of .1 g. of the acetate of the oxime (XXI),
2 cc. of 95 per cent alcohol, 5 cc. of water and 2 cc. of !
2N sodium hydroxide was heated for fifteen minutes. This
was followed by dilution with 4 cc. of water and acidifica
tion using solid carbon dioxide. A precipitate was formed,
which upon recrystallization from alcohol-water yielded
white crystals, m.p. 127° -128°. A mixture of this product
and the oxime gave no m.p. depression.
Attempt to prepare 4-aminothianaphthene from 4-keto-
4,5,6,7-tetrahydrothianaphthene azine (XXII).— (a) Azine of
4-keto-4,5,6,7-tetrahydrothianaphthene (XXII) (19)* To
4.5 g. of 4-keto 4,5,6,7-tetrahydrothianaphthene (IV) dis
solved In 5 cc. of 95 per cent alcohol were added 1 g. of
85 per cent hydrozine hydrate and 1 drop of concentrated
hydrochloric acid. The mixture was refluxed for one hour
l
after which it was poured into 25 cc. of water and allowed ,
to cool. This mixture was then shaken with 200 cc. of 20
per cent hydrochloric acid and filtered, leaving 3 g* (70$) '
of the yellow 4-keto-4,5,6,7-tetrahydrothianaphthene azine
(XXII), m.p. 1956 — 202®.
21 '
(b) Attempt to convert 4-keto-4,5,6,7-tetrahydrothia-
naphthene azine (XXII) to 4-amlnothlanaphthene (19)• One
gram of the azine (XXII) and 0.8 g. of 5 per cent palladium :
on carbon catalyst were added to 4 cc. of phenyl ether and
refluxed for forty minutes. After cooling and filtering,
the solid material was washed with warm benzene. The fil- ,
trate was then distilled until 5-10 cc. of benzene remained.
| f
The remaining solution was then shaken with two 15 cc. por- ;
tions of 10 per cent hydrochloric acid. To the acid extrac-
, tions 10 per cent sodium hydroxide was added until the so
lution became turbid. After the addition of 13 cc. of 5
; per cent hydrochloric acid the turbidity disappeared. Three
cc. of acetic anhydride was then added and the flask shaken :
and warmed. A solution of 4 g. of sodium acetate in 16 cc.
of water was added and the mixture allowed to stand over
night in the refrigerator. No solid anilide was formed.
Attempt to prepare 4-hydroxy-4-carboxy-4,5,6,7-
tetrahydrothlanaphthene (20).— Six grams (.04 mole) of 4-
keto-4,5,6,7-tetrahydrothianaphthene was mixed with 18 g.
(.28 mole) of potassium cyanide. The mixture was covered ;
with 25 cc. of dry ether and cooled in an ice-salt bath.
To this mixture was added 30 cc. of glacial acetic acid
followed by an equal volume of water. After shaking and
standing in the refrigerator for forty eight hours the ether*
22 ,
was evaporated leaving a yellow oil atop the aqueous layer.
The water and oil were separated and the aqueous layer
shaken with 25 cc. of ether. The combined ether-oil extract
was placed in a porcelain dish. After the ether was evaporat
ed, 20 cc. of concentrated hydrochloric acid was added, and
I
the mixture allowed to stand overnight in the refrigerator.
This was followed by heating on a steam bath during which
time an additional 30 cc. of concentrated hydrochloric acid
was added. This caused the appearance of a brown oil. When
sodium carbonate was added this oil did not dissolve, in
dicating that the acid had not been formed.
CHAPTER IV
SUMMARY
Twelve new thianaphthenes derivatives, all involving
substitution at the heretofore difficulty accessible 4-
position of the thianaphthene nucleus, have been prepared.
Compounds obtained with a completely aromatized thianaph
thene nucleus were 4-methylthianaphthene, 4-phenylthia
naphthene, 4-phenylthianaphthenyl-l-dioxide and 4-thia-
naphthenylacetic acid. Hydroaromatic derivatives prepared
were 4-hydroxy-4-methyl-, 4-hydroxy-4-phenyl-, 4-amino-,
4-acetamido-, and 4-benzamido-4,5,6,7-tetrahydrothianaph-
thene, as well as the oxime and the acetate of the oxime of
4-keto-4,5,6,7-tetrahydrothianaphthene.
The Grignard, Reformatsky, and Leuckart reactions
were successfully applied in the preparation of the above
mentioned 4- substituted thianaphthenes via 4-keto-4,5,6,7-
tetrahydrothianaphthene, while the Horning, Schroeter and
cyanohydrin reactions failed to produce 4-substituted thia
naphthenes .
B I B L I O G R A P H Y
BIBLIOGRAPHY
1. Fieser and Kennelly, J. Am. Chem. Soc., 57, l6l6 (1935)*
2. Fries, Ann., 527? 83-114 (1936).
3. Bloch et al., Helv. Chim. Acta, 28, 1406-1410 (1948).
4. Martin, J. Am. Chem. Soc., 5 8, 1438 (1936).
5. ’ ’Newer Methods of Preparative Organic Chemistry," Inter
science Pub. Inc., New York, 1948, p. 36 2.
6. Fieser, L. F., "Experiments in Organic Chemistry," 2 ed.,
John Wiley and Sons, New York, 19^1, p. 455*
7. Fieser, L. F., "Experiments in Organic Chemistry," 2 ed.,
John Wiley and Sons, New York, 19?1, p. 111.
8 . Fieser, L. F., "Experiments in Organic Chemistry," 2 ed.,
John Wiley and Sons, New York, 1941, p. 458.
9. Arnold and Collins, J. Am. Chem. Soc., 62, 983 (1940).
10. Ingersoll, et al., J. Am. Chem. Soc., 5 8, 1808 (1936).
11. Crossley and Moore, J. Org. Chem., 9, 529 (1944).
12. Bordwell, Lampert, et al., J. Am. Chem. Soc., 7.1, 1702
(1949).
1 3. Shriner and Fuson, "The Systematic Identification of
Organic Compounds," 3 ed., John Wiley and Sons, New
York, 1948, p. 177-
14. Barclay and Campbell, J. Chem. Soc., 530-533 (1945)«
15* "Organic Reactions," Vol. I, John Wiley and Sons, New
York, 1942, p. 17.
16. Schroeter, Ber., 6 3, 1308 (1930).
r
1 7. Shriner and Fuson, "The Systematic Identification of
Organic Compounds," 3 ed., John Wiley and Sons, New
York, 1948, p. 202.
18. Melsenheimer, Ber., 54, 3213 (1921)- 1
19* Horning and Horning, J. Am. Chem. Soc., 6 9, 1907 (1947)-
20. Lapworth, J. Chem. Soc., 79? 382 (1901).
Univorslty of Southern California Library

Asset Metadata

Creator Frisch, David M (author)

Core Title The synthesis of 4- substituted thianaphthenes

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Degree Master of Science

Degree Program Chemistry

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