Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- ~60~g9
This invention relates to novel cycloalkanollb]-
thienylurea compounds which may be represented by formula
below:
X
Rl-7-C-N~-R2
R ~ ~ ~ R4
wherein X is a divalent oxygen or divalent sulfur; Y is a
divalent moiety of the formulae:
\/ \~ \ ~
CH2 ' CH or Cl ;
. OH O
Rl is hydrogen or alkyl straight or branched Cl-C4, R4 is
hydrogen or alkyl Cl-C4; R5 is hydrogen, chloro, bromo or
iodo; R~ is hydrogen or alkyl Cl-C4; R2 is selected from the
group consisting of the substituents listed in Table I below:
~ J
- ~06~ 9
T E_
. ..._ _
R2
..~
hydrogen
alkYl Cl-C12
cycloalkYl C3-C6
allyl
. methallyl .
2-butenyl
2-propynyl
hydroxy
alkoxY Cl-Cs
allyloxy
methallyloxy
2-butenylcxy
. methoxymethyl
; -o-cH?-cQoH
phenoxy .
: ben~vloxy
~0 , , .
--CH2-CH2--OH
-CH2-CH2-O-cH~
-CH2-CH2-S-CH3
-CH2-CH(OR)~
~ -CH2-CF3
. -CH2-CN
-CH2-C02R
-NH-CO~R
O
-C-R
O
~1
-C-CC13
~ _ , , ~-:
~:
r~ ~r~ff~ y~p~ ~r~ ~D~ rsi~ ob`;r D~
99
Table I - Continued
-
R2
5 ~
~C1~2-
~ l~L C-NH-
~LCI~2-
~b
~I
NH-C-NH-CH2-
20 1 ~b
[~ CH 2 -
2 5 I~L CH2-CH2-
,~ ~ CH2 I n~
iD3
1~6~)899
wherein ~in ~able I) R is al~;yl Cl-C4, n is ~), 1 or 2, and Q
is selected ~rom the group consiC~ting of the suh~tituent~
listed in Table II below:
TABLE II
_ _
. ........ ~
n a O n a 1 n = 2
.~__
hydrogen hydrogen hydro~en
3,4-methylenedioxy 4-chloro
3- or 4-methoxy 4-methoxy
4-ethoxy 3,4-methyl-
. enedioxy
4-chloro .
4-butoxy
4-methylthio
2,4-dimethyl
2,5-dimethoxy
2,4-dichloro
4-nitro
2-methyl-4-bromo _. _
and R2 and R3 taken togather with the associa~ed N(itrogen)
is selected from the group consisting of morpholino, piperi-
dino, pyrrolidino, 4-phenylpipera~ino, 4-(4-me~hoxyphenyl)-
piperazino, 4-carbethoxypiperazino, 4-oxopipera~ino, 1,2,3,4-
-tetrahydroquinolino and the moiety of the formula.
/
O
..i
Some of the novel compounds of the present inven-
tion may be readily prepared by reacting an appropriately
substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (VII)
with an appropriately substituted isocyanate or isothiocya-
: nate ~YIII) as set forth in the following reaction scheme:
NH-Rl
, R6-- ~R4
: 25 R5 ~ S ~ ~ Y J + R2-N=C=X
(VIII)
: (VII)
x
Ii / .
Rl-N-C-NI~-R2
R6 ~R4
S~ Y (VI )
L~i
)89~
I wherein X, Y, Rl, R2, R~, R5 and R6 are as hereinabove de-
f fined. The reaction can be carried out usin~ approximately
equimolar amounts of the isocyanate or isothiocyanate and
the amine or amine acid salt; however, it is generally pre-
ferable to employ from 5% to 50% excess of the isocyanate or
isothiocyanate wherein the tetrahydrobenzo ring does not con-
tain a hydroxyl group. The reaction can be conducted at at-
mospheric or superatmospheric pressure at a temperature in
the range of 0C. to 100C., but is preferably conducted at
atmospheric pressure at 0C. to 70C. in the presence of an
organic solvent. Suitable organic solvents include aprotic
aromatic solvents such as benzene, toluene, and xylene;
chlorinated hydrocarbon solvents such as methylene chloride,
chloroform, and dichloroethane; ethers such as tetrahydro-
furan, diethyl ether, dimethoxyethane, diethylene glycol di-
methyl ether/ and dioxane; lower alkyl Cl-C4 ketones such as
acetone, methyl ethyl ketone, methyl butyl ketone, and methyl
isobutyl ~etone, or mixtures of said solvents~
When the above reaction is carried out using a
4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine acia salt, it is
desirable to add an acid acceptor to the reac*ion mixture.
Suitable acid acceptors include trialkylamines ~uch as tri
ethylamine, trimethylamine, pyridine or the like; alkali metal
carbonates such as sodium and potassium carbonate; alkaline
earth metal carbonates such as calcium carbonate7 strong basic
ion exchange resins; and aqueous alkali in a 2-phase system
using an immiscible hydrocarbon solvent such as benzene or
toluene, or a chlorinated hydrocarbon such as chloroform or
dichloroethane.
Formula (I) 4,5,6,7-tetrahydrobenzo[b]thien-4-yl-
urea compounds wherein R2 and R3 are hydrogen may be advan-
tageously prepared from the above-identified amine (VII) or
its acid salt by reacting said amine with an approximately
6 _
10~99
equimolar amount of ~odium or potassium cyanate or thiocya
nate. However, it is yenerally preferable ~o employ 5% to
~ 50~ excess of the cyanate or thiocyanate wherein the tetra-
:: hydrobenzo ring does not contain a hydroxy ~roup. The reac-
tion can be conducted under the conditions described above
in detail. Suitable solvents include water, poIar solvents
such as Cl-C3 alcohols, tetrahydrofuran, dioxane, ethylene-
glycol dimethyl ether, diethylenP glycol, dimethyl ether,
acetone, methyl ethyl ketone and the like and mixtures there-
of; in the pH range of 5 ko 7 and preferably at pH 6.
Certain of the formula (I) 4,5,6,7-tetrahydrobenzo-
[b]thien-4-ylurea compounds (XI) may be readily prepared by
reacting approximately equimolar amounts of an appropriately
substituted 4,506,7-tetrahydrobenzo[b]thien-4-yl isocyanate
or isothiocyanate (IX) and an appropriately substituted
R2R3NH amine (X) or its acid-addition salt. The reaction can
be graphically illustrated as follows:
N=C=X
R ~ ~ ~ H-N
(IX) tX)
X
11 ~ R2
(XI)
wherein X, Y, R2, R3, R~, R5 and R6 are as hereinabove de-
fined; with the proviso that Y is not -CHOH. In practice,
the reaction i5 usually conducted with a slight excess (i.e.
up to 20% excess) of ~he amine in the presence of a solvent,
such as described above. Althou~h khe reaction ~ay be con~
-7-
~6~ 9
ducted at superatmospheric pressure and temperatures as high as 100C.,
it is generally preferable to conduct the reaction at atmospheric pressure
at a temperature between 0C. and 80C. When a R2R3NH amine acid salt is
used it is mlost beneficial to introduce into the reaction mixture an acid
acceptor such as described above. When an aqueous or a Cl-C3 alcoholic
ammonia or amine solution is used in the above reaction sequence, then the
formula (XI) co~,pounds are obtained wherein R2 and R3 are as defined above.
Preparation of the isocyanates (IX) utilized in the above reaction
is readily accomplished by reacting the appropriate 4,5,6,7-tetrahydrobenzo-
[b~]thiophen-4-amines or their acid salts with phosgene, preferably under
anhydrous conditions and under a blanket of inert gas such as nitrogen. The
reaction is initially carried out at a temperature between about 0C. to 40C.,
preferably 10C. to 20C., and then heated to between about 50C. and 100C.,
and preferably to from 60C~ to 80C. The reaction is usually also conducted
in the presence of an organic solvent such as benzene, toluene or xylene.
The isothiocyanates (IX) can be prepared by reacting the appropriate 4,5,6,7~-
tetrahydrobenzo[_]thiophen-4-amines with equimolar amounts of carbon disulf-
ide, triethylamine, and a carbodiimide represented by the formula: G-N=C=N-G
where G is cyclohexyl, cycloheptyl, alkyl C4-C6 or the like. This reaction
is generally conducted in the presence of a solvent such as tetrahydrofuran
or an ether such as diethyl ether, at a te~lperature between about -10C. and
~25C. The product can be isolated by distillation or by dry-colu~!n chrom-
atography. Alternatively, the formula (IX) isothiocyanates can be prepared
by the reaction of l,l'-thiocarbonyldiimidazole with 4,5,6,7-tetrahydro-
benzo~_]thiophen-4-amines in the presence of chloroform at ambient temper-
ature. The reaction may be illustrated as follows:
Ll~
~6~9
NH-Rl
I N~ S ~=== N
6 ~ ~ 4 + ~ ) - C - N
(VII) Rl-N-C=S (CHC13)
(XII)
wherein Rl, R4, R5 R6 and Y are as defined above.
Advantageously, formula (I) 4,5,6~7-tetrahydrobenzo[b]-
thien-4-ylurea compounds, wherein Y is carbonyl may be readily pre-
pared from the corresponding type ~I) compounds, wherein Y is methylene
I (XIII) by an oxidation reaction, as set forth in the following reaction
scheme:
R -N-CX-NR R
1 1 2 3 Rl-NI-CX-NR2R3
R~r~(~R4 R5~1_ R4
(XIII)
(XIV)
LE~I
~l~160~
The oxidation is carried out by treating a compound of formula
(XIII) with a 2 to 8 mole equivalent and pre~erably with a 4 to 5 mole
equivalent of
~ -10-
~6~899
an oxidizing agent selected from the group consisting of
ceric ammonium nitrate, silver oxide, or sodium bichromate,
at a temperature between about 0C. and 100C., and prefer-
ably 20C. to 60C., in a solvent selected from the group
consisting of aqueous solutions of acetic acid, acetonitrile,
tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol
dimethyl ether, which may contain nitric acid, phosphoric
acid or perchloric acid; or the oxidizing a~ent chromic anhy-
dride in acetic anhydride followed by hydrolysis.
Furthermore, formula (I) 4,5,6,7~tetrahydrobenzo-
[b]thien-4-ylurea compounds wherein Y is carbonyl (XVIII)
can also be prepared by the above described oxidative process
as set forth in the followin~ reaction scheme:
--~ ... , ., ,, _ ,,,, _ _ .
NH-CHO NH-CHO
R6~--R,~ R6~ 4
( X~7 ) ( `~VI )
X
Il ~R2
H-N-C-N ~T~2
R6 ~ R4~ R5 ~ ~ R~q
o O
(XVIII) (X~7TT)
wherein Z is methylene or hydroxymethylene and X, R2, R3, R4,
R5 and R6 are as hereinabove defined. Upon completion of
the oxidation step, the resulting 7-oxo compounds (XVI) are
hydrolyzed in dilute mineral acid. The thus-obtained amine
(XVII) acid-addition salts are then reacted with an isocyanate
or an isothiocyanate at p~ 5-7 as herein~efore described in
-/!
~L~6~1!39~
detail to yield the desired ureas or thioureas (XVIII).
The corresponding 7-hydroxy analogs are prepared from
the corresponding formula ~I) compounds wherein Y can be only car-
bonyl by reduction with equimolar or excess amounts of sodium boro-
hydrideJ at a temperature range between about 0C. and 75C., pre-
ferably 20 - 40C., in Cl-C3 alcohols to afford a mixture of the
cis and trans isomers. All of the hereinabove described processes
for the preparation of formula (I) 4,5,6,7-tetrahydrobenzo[b]thien-
4-ylurea compounds yield racemic (dl) mixtures. Should the op-
tically active isomers of type (I) compounds be desired, these may
be conveniently obtained by the resolution of the racemic (dl)
amines with (R) - ~)- and (S)-(-)-N-benzoylglutamic acids, re-
spectively in sequence, and using the thus obtained optically
active amines in one of the hereinbefore described reactions
leading to 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea compounds of
the present invention.
~ - 12 -
'~
89g
l`he compounds of this invcntion are useful as
growth--promoting agents for animals such as poultry, fur-bear-
ing and farm animals, and the use of said compounds for this
purpose provides the added advantage of improving feed con-
version for said animals. As used herein, the term "feedconversion" means the ratio of unit weight of feed per unit
weight of gain and improvement in feed conversion means in-
creased weight gain from a given unit of feed consumed.
In practice, a growth-promoting amount of a formula
(I) 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea or an optically active
isomer is administered to a host animal usually in, or with,
the animal's feed. However, said compound may also be ad-
ministered as a subcutaneous implant under the skin of said
animal or as a parenteral injection. When administered in the
- 15 feed of chickens, turkeys, sheep, cattle, yoats, and the like,
usually about 0.0001~ to 0.08~ by weight, and preferably
0.001% to 0.04% by weight of the formula (I) urea, is
effective for increasing gro~th rate and improving feed
conversion. When administered to said animals as a parenteral
- 20 injection or subcutaneous implant, usually in amoun~s that
will supply about 0.001 mg. to 0.2 mg. and preferably 0.005
mg. to 0.10 mg. per kg. of body weight per day of the active
compound, will produce the desired improvement in weigh~t gain
- and enhance food conversion.
In tests conducted with day old chicks, it was
found, that from 1 ppm to 9 ppm of 4,5,6,7-tetrahydrobenzo[~]-
thien-4-ylurea administered in the chick feed produced a
3.3~ to 6.6% improvement in weight gain over untreated con-
trols, and likewise produced a 2.7~ to 4.7~ improvement in
feed conversion. Il
if
8~
The compounds of this invention are also useful as
herbicidal agents. They are effective for controlling un- ~
desirable broadleaf and grass weeds when applied to soil con- r
taining seeds of said undesirable weeds, or when applied to
the foliage of such plants. Usually about 5 pounds to 15
pounds, and preferably about 8 pounds to 10 pounds per acre
o~ the active compound, is sufficient to provide control of
the undesirable plants.
The present invention is further illustrated by the
preparation of representative examplas set forth below, as
well as testing data on typical compounds of the invention.
EXAMP~E 1
Preparation of l-methyl-3 (4,5,6,7-tetrahydrobenzo[b]thien-4-
yl)urea
A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetra-
hydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry
benzene is stirred while 1.05 grams (0.01 mole) of triethyl-
amine and 0.7 ml. (excess) of methyl isocyanate are added
successively. Addition of the latter gives rise to an exo- r
therm, and the mixture becomes very pasty. The mixture is
kept at 45C. for one hour, and after cooling to room temp-
erature, the solid is collected, washed thoroughly with ben-
zene and then with water. On drying, this gives 1.7 grams
(81%) of product, melting point 183C. to 186C. Recrystal-
lization from acetone gives 1.23 grams, melting point
187.5C. to 189C.
On a 0.05 mole scale, the crude yield is 83% (9.15
grams), and the product melts at 181C. to 186C. Recrystal-
lization from acetone gives 6.5 grams, mel~ing point 184.5C.
to 187C.
/SG .
'D7 - ,~ -
399
EX~MPLE 2
.
Preparation of l-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-
.
yl)urea
In the manner described in Example 1, ethyl isocya-
nate is allowed to react with 4,5,6,7-tetrahydrobenzo[_]thio-
phen-4-aminehydrochloride to af~ord 10.1 grams o~ 1-ethyl-3-
-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Recrystalliza-
tion of the crude product from 2-propanol-water (9/1) affords
~rystals which are dissolved in chloroform and washed success-
ively with lN sulfuric acid, water and saturated sodiumbicarbonate solution. This gives the desired product, melting
point 184C. to 188.5C. after evaporation of the chloroform.
EXAMPLE 3
Preparation of l-isopropyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
_ . .... .. . . . . .
-4-yl)urea
In a nitrogen atmosphere, 5.35 grams of 4,5,6,7-
-tetrahydrobenzo[b]thiophen-4-amine is stirred in 100 ml. of 5.,,
diethyl ether, and 3.57 grams of isopropyl isocyanate in
40 ml. of diethyl ether is slowly added to afford crystalline
product. The mixture is stirred for an additional 0.5 hour
and then filtered after standing overnight to give 8.3 grams,
melting point 223C. to 226C., of l-isopropyl-3-(4,5,6,7-
-tetrahydrobenzo[_]thien-4-yl)urea.
EXAMPLE 4
Preparation of l-(_-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-
-4-yl)urea
In the manner described in Example 1, 4,5,6,7-tetra-
hydrobenzo[_]thiophen-4-amine is allowed to react with n-hexyl
isocyanate to give l-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[_]-
thien-4-yl)urea, melting point 122C. to 124C.
/5'
r-~ 7 -
L~
~6~)899
EXAMPLE 5
-
Preparation of l-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
~4-yl)uxea
-
In a similar manner, as described in Example 1,
4,5,6,7-tetrahydrobenæo[b]thiophen-4-amine hydrochloride is
allowed to react with cyclohexyl isocyanate in dry tetrahydro-
furan to afford 7 grams of 1-cyclohexyl-3-(4,5,6,7-tetrahydro-
benzo[b]thien-4-yl)urea, melting point 222C. to 225C.
EXAMPLE 6
Preparation of l-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-
-yl)urea
A mixture of 5 grams of methoxyamine hydrochlo~ide 5
in 60 ml. of methylene chloride is cooled to about 15C.,
and 6 grams of triethylamine in 15 ml. of methylene chloride
is added. After 20 minutes, 5.38 grams of 4,5,6,7-tetrahydro-
benzo[b]thien-4-yl isocyanate in 20 ml. of methylene chloride
is added over 20 minutes at 15C. to 20C. After stirring for 3
an hour, the mixture is filtered, and the filtrate is washed
with water and then aqueous sodium bicarbonate solution. The
solution is dried and evaporated to afford a white solid. The
solid is recrystallized from acetone-hexane to afford 5.1
grams, melting point 138.5C. to 141C., of l-methoxy-3-(4,5,
6,7-tetrahydrobenzo[b]thien-4-yl)urea.
Similarly, l-ethoxy-3-(4,5,6,7--tetrahydrobenzo[_]-
thien-4-yl)urea and 1-butoxy-3-(4,5,6,7-tetrahydrobenzo[_]-
thien-4-yl)urea are prepared by using ethoxyamine hydrochloride
and n-butoxyamine hydrochloride, respectively, in place of
methoxyamine hydrochloride.
EXAMPLE 7
Preparation of l-(benzloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-
- -4-yl)urea
In the manner described in Example 6, O-benzyl hy-
- droxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-
.~ .
~C3 6~89~
-4-yl isocyanate are allowed to react to afford l-(benzyloxy)-
-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is re~
crystallized from 95~ ethyl alcohol methyl isobutyl ketone.
Th~ product melts at 96.5C. to 99C.
EXAMPLE 8
Preparation of l-hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo-
. = . _ _ _ . , . .. _ __ .. . _ _ _ _
[ ]thien-4-yl)urea
,
In the manner described in Example 6, N-methylhydroxyl-
amine hydrochloride and 4,5,6,7-tetrahydrobenzo[_]thien-4-yl
isocyanate are allowed to react to afford 1-hydroxy-1-methyl-3-
(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystal-
lized from acetone-hexane-ether to give crystals/ with melting
point 98C. to 102C.
EXAMæLE 9
Preparation of l-methoxy-l-methyl-3-(4,5,6,7-tetrahydrobenzo-
-
[b]thien-4-yl)urea
Following the procedure described in Example 6,
- N~O-dimethyl hydroxylamine hydrochloride and 4,5,6,7-tetra-
hydrobenzo[_]thien-4-yl isocyanate are allowed to react to
give 1-methoxy-1-methyl-3-(4~5,6,7-tetrahydrobenzo[b]thien-
-4-yl)urea, which is crystallized from acetone-hexane-ether
to give product melting at 60C. to 62.5C.
EXAMPLE 10
Preparation of 4,5,6,7-tetrahydrobenzo[_]thien-4-ylurea
A mixture of 50 grams of amine hydrochloride (about
45 grams real, based on 90% purity) in 100 ml. of water is
stirred at about 15C., and a solution of 23.1 grams of
potassium cyanate in 100 ml.-of water is added dropwise. After
- completion of the addition, the mixture is warmed slowly to
70C. to 75C. and held for an hour. The mixture is cooled,
and the white solid is collected by filtration and washed with
water. The solid is air-dried, pulverized, and washed with
acetonitrile. On drying, this gives 37.3 grams of crude pro-
D~
1C~6~)899
duct, which on txeatment with about 1200 ml. of hot acetone
gives 11.45 grams, melting point 200C. to 204C. of the title
compound.
Similarly, 2-methyl- and 3-methyl-4,5,6,7-tetra-
hydrobenzo[b]thien-4-ylurea are prepared to give products
melting at 232-233C. and 227-230C. (dec.~, respectively.
When N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine
hydrochloride is used, l-methyl-1-(4,5,6,7-tetrahydrobenzo[b]-
thien-4-yl)urea, melting point 151.~-154.5C., is obtained.
EXAMPLE 11
Preparation of l-phenethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien
.
-4-yl(urea
A mixture of 3.82 grams of phenethylamine in 100 ml.
of diethyl ether under nitrogen atmosphere is allowed to react
with 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl iso-
cyanate in 25 ml. of diethyl ether vla dropwise additio~ of
the latter solution. After stirring an hour at room tempera-
ture, the mixture is filtered and washed with ether to give 7.9
grams, melting point 163C. to 166C., of l-phenethyl-3-(4,5,
6,7-tetrahydrobenzo[_]thien-4-yl)urea.
In a similar manner, methylamine, ethylamir.e, iso-
propylamine, n-hexylamine and cyclohexylamine are allowed to
react with the aforementioned isocyanate to afford l-methyl-,
l-ethyl-, l-isopropyl-, _-hexyl- and l-cyclohexyl-3-(4,5,6,7-
tetrahydrobenzo[b]thien-4-ylurea.
EXAMPLE 12
Preparation of 1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thlen-
-4-yl)urea
A solution of 6.27 grams of 4,5,6,7-tetrahydrobenzo-
3~ [b]thien-4-yl isocyanate in 200 ml. of diethyl ether is charged
with gaseous dimethylamine introduced via a capillary tube with
stirring. After 0.5 hour of bubbling, the gas flow is termin-
ated, and the mixture is evapor~ated to dryness to give a solid
!;~
1~6~)899
residue. This is crystallized from acetone-hexane-ether to
give l,l-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-
urea melting at 117C. to 120C.
The identical product is obtained when 4,5,6,7-
-tetrahydrobenzo[b]thiophen-4-amine is allowed to react with
equivalent amounts (or excess) of dimethylcarbamoyl chloride
and triethylamine in dimethylformamide. The reaction mixture
is stirred for several hours and then filtered. The filtrate
is evaporated to dryness and the residue is purified by
10 crystallization from acetone-hexane to afford the title com-
pound.
EXAMPLE 13 F
Preparation of l-benæyl-3-(4,5,6,7-tetrahydrobenzo~b]thien 4- t
-yl)urea
In the manner described in Example 6, except for the
use of diethyl ether instead of methylene chloride, l-benzyl-
-3-(4,5,6,7-tetrahydrobenzo[_]thien-4-yl)urea is obtained by
allowing benzylamine and 4,5,6,7-tetrahydrobenzo[b]thien-4-
-yl isocyanate to react. The product melts at 211C. to
214C.
The title compound is also obtained by allowing
benzyl isocyanate to react with 4,5,6,7-tetrahydrobenzo[_]-
thiophen-4-amine in ether. t
EXAME'LE 14
Preparation of l-hydroxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-
a
-4-yl)urea
The above compound is prepared in the manner
described in Example 6, by allowing 4,5,6,7-tetrahydrobenzo-
[b~thien-4-yl isocyanate to react with hydroxylamine hydro-
chloride in the presence of triethylamine. The product melts
at 158.5C. to 160.5C.
.. /~
.. ,
)899
EXAMPLE 15
i
Preparation of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-
~ . _
-morpholinecarboxamide
In the manner outlined in Example 6, except for
using diethyl ether instead of methylene chloride, 4,5,6,7-
-tetrahydrobenzo[b]thien-4-yl isocyanate is allowed to react
with morpholine to give N-(4,5,6,7-tetrahydrobenzo[b]thien-
-4-yl)-4-morpholinecarboxamide, which mel-ts at 152C. to
154C.
EXAMPLE 16
Preparation of 2-bromo-4,5,6,7-tetrahydrobenzo[b~thien-4-ylurea
A sample of 7.84 grams of 4,5,6,7-tetrahydrobenzo-
[b]thien-4-ylurea is dissolved in 72 ml. of acetic acid, and
24 ml. of water is added. Bromine (2.3 ml. or 7.05 grams) in
32 ml. of acetic acid is added dropwise. The mixture is
stirred at room temperature for 0.5 hour, and then 7.23 grams
of sodium acetate in 40 ml. of water is added. An additional
120 ml. of water is added and stirring is continued for 0.5
hour. The white solid is collected, washed with water and
cold sodium acetate solution to give 9.8 grams, melting point
206.5C. to 209.5C., of 2-bromo-4,5,6,7-tetrahydrobenzo[b]-
thien-4-ylurea.
EXAMPLE 17
Preparation of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[_]thio-
phen-4-amine
A sample of 54.3 grams of N-formyl-4,5,6,7-tetra-
hydrobenzo[b]thiophen-4-amine is stirred in 270 ml. of acetic
acid and 90 ml. of water. Bromine ~53 grams) in 120 ml. of
acetic acid is added gradually. After stirring for 0.5 hour
at room temperature, 61.5 grams of sodium acetate in 225 ml. of
water is added. -More water is added, and the mixture is ex-
tracted with ether. Methylene chloride is added to the ether
solution to prevent crystallization, and the solution is
. A 7 ~
106089~
evaporated to dryness. The residue is crystallized from
acetone-hexane-ether to afford 61 grams, melting point 104C.
to 108C., of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thio- ~
phen-4-amine.
EXAMPLE 18
. _
Preparation of 2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]-
-
thiophen-4-amine
-
A mixture of 40.9 grams o~ 2-bromo-N-formyl-4,5,6,7-
-tetrahydrobenzo[b]thiophen-4-amine, 16.2 grams of cuprous
cyanide and 47 ml. of dry dimethylformamide is heated at re-
flux temperature for 4 hours, and then cooled to about 60C.
and poured into 270 ml. of water. The mixture is extracted
with toluene several times, and the toluene extracts are
washed with 1.2N hydrochloric acid and saturated sodium chloride
respectively. On drying, 5.7 grams of crude product is ob-
tained. The aqueous mother liquor is treated with 97.3 grams
` of ferric chloride hexahydrate and 30 ml. of concentrated
hydrochloric acid and shaken. It is then extracted with tol-
uene several times, and the extracts are washed further with
1.2N hydrochloric acid, saturated sodium bicarbonate solution
and brine, respectively. On drying and evaporation of
toluene, an additional 2.5 grams of product is obtained. The
two crops are combined and recrystallized from acetone-hexane
to afford 4.8 grams of 2-cyano-N-formyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-4-amine, melting point 131C. to 134C.
EXAMPLE 19
Preparation of 2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-4-
~.
-amine hydrochloride
.
A mixture of 4.~ grams of 2-cyano-N-formyl-4,5,6,7-
-tetrahydrobenzo[b]thiophen-4-amine in 70 ml. o~ lN hydro-
chloric acid is refluxed for an hour and evaporated to dryness
to afford 4.7 grams of 2-cyano-4,5,6,7-tetrahydrobenzo[b]thio-
phen-4-amine hydrochloride, melting point 241C. to 246C.
`j .(~ ,1 ~f
~o~99
~dec.).
EXAMPLE 20
Preparation of 2-cyano-4,5,6,7--tetrahydrobenzo[b]thien-4-ylurea
The desired product, 2-cyano-4,5,6,7-tetrahydrobenzo-
~b]thien-4-ylurea, is prepared in the manner described in Ex-
ample 10 by allowing 2-cyano-4,5,6,7-tetrahydrobenzo[b]thio-
phen-4-amine hydrochloride to react with potassium cyanate.
The crude product melts at 210C. to 214C., and the product
which is recrystallized from nitromethane melts at 209C. to
213C.
EX~lPLE 21
.
Preparation of 2-chloro-4,5,6,7-tetrahydrobenzo[b~thiophen-4- r
-amine
A sample of 11.4 grams 4,5,6,7-tetrahydrobenzo[b]-
thiophen-4-amine hydrochloride is stirred in 150 ml. of chloro- L
form at about 10C., and 6.1 ml. of sulfuryl chloride is added r
dropwise. The mixture is stirred for 3.5 hours at room temp-
erature, and then about 20 ml. of 50% sodium hydroxide solu-
~- tion is added gradually to dissolve the suspended solid. The
mixture is then poured into water and extracted with chloro-
form twice. The extracts are dried, evaporated to dryness,
and the residue is distilled to give 7.4 grams of 2-chloro-
-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, boiling point 94C.
to 98C/o.5 Torr.
EXAMPLE 22
Preparation of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thien-4-yl-
- -urea
The desired product, 2-chloro-4,5,6,7-tetrahydroben-
zo[b]thien-4-ylurea, is prepared in the manner described in Ex-/ `
ample 31 by allowing 2-chloro-4,5,6,7-tetrahydrobenzo[b]thio-
phen-4-amine to react with hydrocyanic acid ln situ. The pro-
duct melts at 194C. to 198C.
899
EXAMPLE 23
.
Preparation of N-~2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-
yl)acetamide
.
N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine
(19.5 grams) is stirred in 300 ml. of methylene chloride in a
nitrogen atmosphere, and 17 ml. of acetyl chloride is added.
The mixture is cooled to about 10C., and 28.1 ml. of stannic
chloride is added slowly. After stirring for 1.5 hours at
room temperature, the mixture is cooled to about 10C., and
450 ml. of 1.2N hydrochloric acid is added. The mixture is
shaken, and the methylene chloride solution is separated and
washed with lN hydrochloric acid, followed by saturated 50~ r
dium bicarbonate solution. On drying and evaporating to dry-
ness, crystals are obtained. Recrystallization from acetone-
-hexane gives 15.4 grams, melting point 167.5C. to 172C., of
N-(2-acetyl-4,5,6,7-tetrahydrobenzo[_]thien-4-yl)acetamide.
EXAMPLE 24
Preparation of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-
- -amine hydrochloride
The product from Example 23 (7.25 grams) is heated
with 90 ml. of lN hydrochloric acid at reflux temperature for
8.5 hours and cooled. The mixture is diluted with water and
extracted with methylene chloride. The aqueous layer is then
evaporated to dryness using 2-propanol for facilitating removaL
of water. This gives 4.85 grams of 2-acetyl-4,5,6,7-tetra-
hydrobenzo[b]thiophen-4-amine hydrochloride.
EXAMPLE 25
- Preparation of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl-
-urea
A sample of 6.3 grams of 2-acetyl-4,5,6,7-tetrahydro-
benzolb]thiophen-4-amine hydrochloride is dissolved in 35 ml.
of water and cooled to 15C. A solution of 2.64 grams of
potassium cyanate in 35 ml. of water is added, and after 0.5
--,35 --
. ~
1~6~899
hour the mixture is heated at 70C. for about 40 minutes. The
mixture is cooled, and the solid ls collected and washed with
water. On drying, 5.55 grams, melting point 218C. to 220C.,
- of 2~acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is ob-
tained.
EXAMPLE 26
Preparation of l-ethyl-3-(4,5,6,7-tetrahydrobenzolb]thien-4-
-yl)thiourea
A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[_]-
thiophen-4-amine hydrochloride is stirred in 100 ml. of dry
tetrahydrofuran, and 6.06 grams of triethylamine is added.
After stirring for 15 to 30 minutes, 5.23 grams of ethyl iso-
thiocyanate in 20 ml. of dry tetrahydrofuran is added drop-
wise, and the mixture is heated for 2 hours at 50C. The
mixture is cooled and filtered, and the filter cake is washed
with hexane. The filtrate is evaporated to dryness and poured
vn ice. The oil is extracted with ether, and the extract is
washed with lN sulfuric acid, water, and saturated sodium
bicarbonate solution. The ether extract is dried and evaporated
to dryness to afford an oil. This oil crystallizes in ether
to afford l-ethyl-3-(4,5,6,7-tetrahydrobenzo[_]thien-4~yl)-
thiourea, melting point 106C. to 112C.
Similarly, use of methyl isothiocyanate, butyl iso-
thiocyanate and cyclohexyl isothiocyanate affords 1-methyl-,
l-butyl- and 1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
-4-yl)thioureas.
EXAMPLE 27
Preparation of 4,5,6,7-tetrahydrobenzo[_]thiophen-4-amine
A sample (61.2 grams) of 4,5,6,7-tetrahydrobenzo[b]-
thiophen-4-amine hydrochloride is suspended in 150 ml. of r
water, and about 400 ml. of 10~ aqueous ammonium hydroxide is
added to the mixture. The alkaline mixture is then extracted
twice with ether, and after drying the ethereal solution is
~ 7 _ ~ _
~o~
evaporated to dryness. The amine is then distilled to give
40.9 grams, boiling point 100C. to 102C. at 3 Torr., of
4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine.
EXAMPLE 28
Preparation of (-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium
(R)-N-benzoyl glutamate
A mixture of 8.04 grams of (R)-(~)-N-benzoyl glut-
amic acid in 1.92 grams of acetic acid and 80 ml. of water is
heated on a steam bath until a solution is obtained. This hot
solution is stirred while 9.80 grams of 4,5,6,7-tetrahydro-
benzo[b]thiophen-4-amine is added gradually. About 2 ml. of
ethanol is used in the transfer as a rinse for the amine.
The mixture is then allowed to cool to room temperature and to
stand overnight. The mixture is cooled in a refrigerator,
filtered to collect the crystals, and the filter cake is washed
with water several times. On drying, this gives 9.27 grams
of the title salt, melting point 192C. to 194C.;
589 ' [a]436 -44.6, [a]365 -71.4 at c = 4.475
in acetic acid.
The original filtrate is concentrated under reduced
pressure to a small volume and partitioned between diethyl
ether and aqueous sodium hydroxide. The aqueous base is ex-
tracted with ether, and this ether extract is combined with the
first ether fraction. This is then dried over magnesium
sulfate, evaporated to dryness to afford the recovered amine,
and the amine is added to a stirred, hot solution of 8.04
grams of (S)-~-)-N-benzoyl glutamic acid in 1.92 grams of
- acetic acid and 80 ml. of water. Crystallization occurs rap-
idly, and after 10 minutes of heating on a steam bath, the
mixture is allowed to cool in a refrigerator. The crystals
are collected, washed with water and dried to afford 11.1
grams of (+)-4,5,6,7-tetrahydrobenzo[b]thiophene-4-ammonium
(S)-N-benzoyl glutamate salt, melting point 192C. to 193.5C.;
... .
)89~
[a]589 +12-2~ ~]436 + 42-7, [a~365 + 82 at c = 4.35
in acetic acid.
EXAMPLE 2 9 r
Preparation of t-)-4,5,6,7-tetrahydrobenzoEb]thien-4-ylurea
The salt (8.8 grams of 4,5,6,7-tetrahydrobenzo[_]-
thiophen-4-amine (R)-(+)-N-benzoyl glutamic acid) is added
to ice water mixture is a separatory funnel, and 3.5 grams of
sodium hydroxide in 55 ml. of water is added. The mixture is
shaken until a solution is obtained, and then is extracted
with diethyl ether twice. The ether extracts are washed with
saturated sodium chloride solution, and with ice added the
mixture is extracted with 2.36 ml. of concentrated hydrochloric P
acid in 25 ml. of water. The acid layer is then treated with
2.29 grams of potassium cyanate in 30 ml. of water at 20C.
After stirring for an hour, the mixture is heated ~o 0.5 hour
and cooled. The product is collected by filtration, wasned
with water, and dried to give 2.75 grams, melting point
218.5C. to 221.5C.; 1~]25 -63.2, ~]436 -149-9~ [~]365
-271.5, of (-)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
Similarly, the salt o~ 4,5,6,7-tetrahydrobenzo[b]-
thiophen-4-amine and (S)-(-)-N-benzoyl glutamic acid is treated
in the above manner to afford (+)-4,5,6,7-tetrahydrobenzo[b]-
thien-4-ylurea, melting point 218C. to 220C.; [a]5859 +60,
[~]436 +149.8, [~]365 +272.5o.
EXAMPLE 30
Preparation of 4,5,6,7-tetrahydrobenzo[_]thien-4-yl isocyanate
A sample of 47.6 grams of 4,5,6,7-tetrahydrobenzo[b]-
thiophen-4-amine hydrochloride is stirred in 150 ml. of water,
and 350 ml. of 10~ sodium hydroxide is added. The mixture is
shaken and extracted with benzene twice. The extract is dried
and evaporated to dryness to afford the amine, which is stored
under nitrogen. The amine is then added dropwise to 866 ml.
of 12.5% phosgene solution (benzene) in nitrogen atmosphere at
.. . . .. _ . _ . _ _ .. . _ . . ... . . . .
399
20C. Af~er stirring for an hour at room temperature, the
mixture is gradually heated to 60C. and kept at this temp-
erature for 7 hours. The mixture is cooled to room temperature
and evaporated to dryness to afford a residue, which is
distilled to give 22.4 grams, boiling point 98C. to 101C/-
0.6 Torr., of 4,5,6,7-tetrahydrobenzo~b]thien-4-yl isocyanate.
EXA~LE 31
Preparation of 4,5,6,7-tetrahydrobenzo[b~thien-4-ylurea
A sample of 4,5,6,7-tetrahydrobenzo[_]thiophen-4-
-amine (19.9 grams) is cooled in a flask, and a solution of
12 ml. of 12N hydrochloric acid in 50 ml. of water is slowly
added. Subsequently, at about 20C., a solution of 11.7 grams
of potasstium cyanate in 80 ml. of water is added in 0.5
hour. The mixture is stirred at room temperature for one hour
- 15 and then warmed to 60C. and kept at this temperature for
0.5 hour. After standing overnight at room temperature, the
product is collected and washed with water to afford 21 grams,
melting point 206C. to 209C.
- EXAMPLE 32
Mouse Growth Regulant Tests
CFI female mice from Carworth Farm are received
when they are six weeks old. They are housed ten to a cage
in air-conditioned rooms (72F. to 76F.) with automatically
controlled lights, 14 hours on and 10 hours off. The basal
diet used in these studies is Purina Laboratory Chow (see
description below), which is supplied ad libitum~ Water is
also allowed ad libitum.
Thirteen days after arrival, the mice are weighed
in groups of ten and assigned at random to the different treat-
ments. The concentration of the different compounds in the
diet is indicated in the following Tables. Twelve days later
the mice are weighed again and the experiment terminated. At
least three cages (30 mice) of untreated controls are included
1~6~)~99
in each test. Test data are provided in Table XI below
wherein data are reported as percent weight gain over controls.
The following is a description of the diet to which the
growth promoting compounds are added.
DIET
1.
GUARANTEED ANALYSIS
Crude protein not less than r ~ 23 ~ 0
Crude fat not less than................. 4.5
Crude fiber not more than............... 6.0
Ash not more than..... O........................ 9.0~
INGREDIENTS 9
Meat and bone meal, dried skimmed milk, wheat
germ meal, fish meal, animal liver meal, dried
beet pulp, ground extruded corn, ground oat
groats, soybean meal, dehydrated alfalfa meal,
cane molasses, animal fat preserved with BHA,
vitamin B12 supplement, calcium pantothenate,
choline chloride, folic acid, riboflavin sup-
plement, brewers' dried yeast, thiamin, niacin,
vitamin A supplement, D activated plant sterol,
vitamin E supplement, calcium carbonate, di-
calcium phosphate, iodized salt, ferric ammonium
citrate, iron oxide, manganous oxide, cobalt
carbonate, copper oxide, zinc oxide.
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899
E~AMPLE_33
Preparation of 4,5,6,7-tetrahydrobenzo[b~thien-4-yl isothio-
.
cyanate
A sample ~47.5 grams) of 4,5,6,7-tetrahydrobenzo[b]-
S thiophen-4-amine hydrochloride is stirred in methylene chloride-
-water and 5% sodium hydroxide solution is added gradually
until the pH is about 10. The methylene chloride layer is re-
moved and the aqueous layer is extracted with methylene chloride.
The organic layers are combined, dried over magnesium sulfate,
and evaporated to dryness to afford the oily amine. The amine
is s~irred in 500 ml. of ethyl acetate under nitrogen atmos-
phere and 25.4 grams of triethylamine is added. After about
15 minutes, 20.9 grams of carbon disulfide is added to afford
a copius precipitate. An additionai 200 ml. of ethyl acetate
is added and the solid is pulverized with a spatula. After an
hour of stirring, 51.5 grams of dicyclohexyl carbodiimide is
added and stirring is continued for an overnight period. Sub-
sequently, the mixture is heated at about 50C. for 2 hours
and cooled. The solid is removed by filtration and washed with
ethyl ace~ate. The filtrate is evaporated to afford a mixture
of solid and mostly oil. The solid is removed by filtration
after either is added. The ether filtrate is evaporated to
dryness to afford the crude isothiocyanate, which is purified
by chromatography on a dry-column of silica gel using 65/35
5 (volume/volume) of petroleum ether/methylene chloride.
EXAMP~E 34
Preparation of N-(4,5,6,7-tetrahydrobenzo[_]thien-4-yl)-4-piper-
idinethiocarboxamide
In 50 ml. of tetrahydrofuran, 5.85 grams of 4,5,6,7-
-tetrahydrobenzo[f]thien-4-yl isothiocyanate is stirred and
2.81 grams of piperidine is added. An exotherm is observed
and the temperature rises to about 40C. to 50C. After 2.5
hours, the mixture is heated at reflux temperature for 3.5
1~608~9
hours. After stirring overnight, the mixture is evaporated
to dryness to afford a sticky yellow-brown solid. Ether is
added to this material and the off-white, insoluble product
is collected. The crude product, 5.25 grams, melts at 102C.
to 10~C.
EXAMPLE 35
The following compounds set forth in Table XII below
are prepared by using the methods described in Example 3 and
Example 5 and using the corresponding amines (diethyl ether
solvent) or amine hydrochlorides (tetrahydrofuran solvent)
with the appropriate isocyanates or isothiocyanates.
Il 11 ~R2
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EXAMPLE 36
Preparation of 4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-
_ . .
-4-amine hydrochloride
2~3-Dimethyl-6,7-dihydro-5H-benzoEb]thiophen-4-one
is prepared in the manner described by Napier and Chu [Inter-
national Journal of Sulfur Chemistry, A, 1, 62-64 (1971)].
This ketone is converted to 4-formylamino-4,5,6,7 tetrahydro-
-2,3-dimethylbenzo[b]-thiophene by the method described by r
Kloetzel, Little, and Fish [Journal of Organic Chemistry, 18,
1511-1515 (1953)]. Hydrolysis of this formamido derivative
is accomplished by using the method described in Example 19
to afford 4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-4-
-amine hydrochloride.
3-Methyl-6,7-dihydro-5H-benzo[_]thiophen-4-one is
prepared similarly and converted to 3-methyl-4,5,6,7-tetrahydro-
benzo[b~thiophen-4-amine hydrochloride by the above sequence.
EXAMPLE 37
Preparation of 2-methyl-3(4,5,6,7-tetrahydrobenzo[b]thiophen-
. . _ _ . _ . . .
-4-amine hydrochloride
2-Methylthiophene is converted to 2-methyl-6,7-
-dihydro-5H-benzo[blthiophen-4-one by the method described
by Fieser and Kennelly [Journal American Chemical Society,
57, 1611 (1935)]. This ketone is further converted to
2-methyl-4,5,6,7-tetrahydrobenzo[_]thiophen-4-amine hydro- r
chloride by the methods cited in Example 36.
EXAMPLE 38
Preparation of l-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-7-
-yl)urea
4,5-Dihydro-6H-benzo[b]thiophen-7-one is prepared
by the method of MacDowell and Greenwood [Journal of Hetero- r
cyclic Chemistry, 2, 44 (1965)] and converted to 4,5,6,7-
- -tetrahydrobenzo[b]thiophen-7-amine hydrochloride, melting
point 209C. to 212C., by the methods cited in Example 36.
~ J ,l
- ~ . .
.. ~
. , _ ~ _ r _ _ _, _ . _ _ -- ~ _ _ _ _ . _ _ . . . _ . _ _ . _ _ . _ _ . _ _
31 060~
The amine hydrogen chloride salt is then treated with potas-
sium cyanate in the manner described in Example 10 to afford
4,5,6,7-tetrahydrobenzo[b]thien-7-ylurea, melting point 211C. ~
to 213C.
Conversion of the amine salt to l-methyl-3-(4,5,6,7-
-tetrahydrobenzo[_]thien-7-yl)urea, melting point 192C. to
195C. is accomplished by using the procedure of Example 7.
EXAMPLE 39
Preparation of 2-nitro-N-formyl-4,5,6,7--tetrahydrobenzo[b]-
-
thien-4-ylurea
_
Acetic anhydride (30.8 ml.) is cooled to -10C. to
-12C. and to the stirred solution is added dropwise 70
nitric acid (4 g. or 44.5 mmol). Over a period of 0.5 hour,
N-formyl-4;5,6,7-tetrahydrobenzo[b]thiophen-4-amine (7.24
grams or 40 mmol) is added and the mixture is allowed to warm
to room temperature over 2.5 hours and poured onto ice-water
mixture (200 ml.). After stirring overnight, the sticky
solid is filtered off and washed well with water. The air- l~
-dried, dark, sticky solid is triturated with ether(~20 ml.), t
and the resulting nitro compound is filtered and washed with
ether (10 ml.). The product, 2-nitro-N-formyl-4,5,6,7-tetra- ~
hydrobenzo[b]thiophen-4-amine, melts at 116C. to 120C. and `,
weighs 3.25 grams.
Hydrolysis of the above formamide is accomplished
by the method described in Example 19 to afford 2-nitro-4,5,6,7-
tetrahydrobenzo[b]thiophen-4-amine hydrogen chloride, melting
point ~260C; infrared spectrum shows NO2 bands at 1520 cm 1
and 1335 cm~l.
Conversion of the amine hydrogen chloride salt to
2-nitro-4,5,6,7-tetrahydrobenzo[_]thien-4-ylurea is accomplish-
ed by the method described in Example 10. It melts at 211C.
with decomposition after recrystallization for MeOH.
'
57
. `~. ` ,~
~06~899
EXAMPLE 40
Preparation of l-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydro-
_
benzo[b]thien-4-yl)urea
By the method of Kloetzel, Little, and Fi~h [Journal
of Organic Chemistry, 18, 1511 (1953)3, 4,5,6,7-tetrahydro-4-
-methylbenzo[b]thiophen-4-ol is prepared and dehydrated with
fused sodiu~ hydrogen sulfate by heating to afford 6,7-dihydro-
-4-methylbenzo[b]thiophen, boiling point 75/0.9 Torr. This
olefin (3 grams) is stirred with 3.9 grams of silver iso-
cyanate in 50 ml. of dry ether under N2 atmosphere at -10C.
and 5.07 grams of iodine is added. After stirring for 1.25
hour at -10C. to 0C. and then at 10C to 15Ç. for 1.5 hours,
the mixture is filtered over diatomaceous earth and the filter
cake is washed with ether thoroughly. The filtrate is then
treated with 2 ml. of 40~ aqueous methyl amine to afford
1.6~ grams, melting point 122C. ~o 123C., of l-methyl-3-(5-
~iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
EXAMPLE 41
Preparation of l-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo-
[_]thien-4-yl)urea
Deiodination of l-methyl-3-(5-iodo-4-methyl-4,5,6,7-
-tetrahydrobenzo[b]thien-4-yl)urea is accomplished by
treating a methanol mixture of this compound with Palladium
on carbon and magnesium oxide in a Paar hydrogenator at 50 psig
After uptake of the hydrogen is completed, the mixture is
filtered through diatomaceous earth and filtrate is evaporated
to dryness to afford l-methyl-3-(4-methyl-4,5,6,7-tetrahydro-
benzoLb]thien-4-yl)urea, melting point 135C. to 145C. I;
E~PLE 42
Preparation of l-methyl-3-(5,6,7,8-tetrahydro-4H~cyclohepta-
[b~thien-yl)urea
5,6,7,8-Tetrahydro-4H-cyclohepta[b]thiophen-4-one
is converted to N-(5,6,7,8-tetrahydro-4H-cycloheptaLb]thien-4-
_~ .
1~ .
1~6~1~99
yl)formamide, melting point 164C. to 166C., by method
described in Example 36 lsecond reference). Hydrolysis of the
formamide is accomplished by the method described in Example
19 to afford 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-
-amine hydrochloride, melting point 233C. to 236C. dec. r
The amine hydrochloride is then converted to l-methyl-3-(5,6,7,
8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, melting point
220C. to 222C., by the method described in Example 35 using
THF as solvent.
Similarly, l-ethyl-3-(4,5,6,7-tetrahydro-4H-cyclo-
hepta[b]thien-4-yl)-2-thiourea with melting point 117C. to
120C. is obtained.
EXAMPLE 43
Preparation of 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-
L
-4-ylurea
By the method described in Example 36 (first refer- r
ence), 7,7,-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one
is prepared and converted to 7,7-dimethyl-4,5,6,7-tetrahydro-
benzo[_]thiophen-4-amine hydrochloride, melting point 211.5C.
to 215C., by the remaining methods described in Example 36.
~he amine hydrochloride is converted to 7,7-dimethyl-4,5,6,7-
-tetrahydrobenzo[b]thien-4-ylurea, melting point 184C. to
189C. dec., by the method described in Example 10.
EXAMPLE 44
Preparation of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-
-4-ylurea
By the method described in Example 36 (first refer-
ence), 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[_]thiophen-4-one
is prepared and converted to 6,6-dimethyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-4-amine hydrochloride ~melting point ~300C.)
by the two remaining methods cited in Example 36. The amine
hydrochloride is then converted to 6,6-dimethyl-4,5,6,7-tetra-
hydrobenzo[_]thien-4-ylurea, melting point 174C. to 178C.,
,
.
~06;0~99
by the method outlined in Example 10.
EXAMPLE 45
Preparation of l~methyl-3-~5-methyl-4,5,6,7-tetrahydrobenzo-
[b~thien-4-yl)urea
_
Diisopropylamine (7.3 grams or 72 mmol) is cooled
and stirred in 60 ml. of dry te1trahydrofuran (THF) and 45 ml.
(72 mmol) of 1.6N n-butyl lithium in hexane is added to
<-5C. Five minutes later a solution o~ 4,5,G,7-tetrahydro-
benzo[b]thiophen-4-one, 12 grams or 60 mmol in 30 ml. of
THF) is added dropwise at 0C. to -10C. After stirring for
30 minutes at room temperature, 38 grams (270 mmol) of methyl
iodide is added at ~30C. After stirring for 40 hours at
room temperature, 100 ml. of water is added and the THF is
removed ln vacuo. The residue is extracted with 3x50 ml. of
methylene chloride and the combined extracts are washed with
50 ml. of 2N hydrochloric acid, 50 ml. of lM sodium carbonate,
and 50 ml. of brine, respectively. The solution is dried
(magnesium sulfate) and evaporated in vacuo to afford 9.46 "
grams of light brown oil. The oil is purified by chromato-
graphy on a silica-gel dry column using 1:1 hexane/methylene
chloride to afford 6.9 grams of 5-methyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-4-one. This ketone is converted to 5-methyl-
-4,5,6,7-tetrahydrobenzo[_] thiophen-4-amine hydrochloride by
the method cited in Example 36 and then the amine hydrochloride
is converted to 1-methyl-3-(5-methyl-4,5,6,7-tetrahydrobenzo- r
[b]thien-4-yl)urea, melting point 173C. to 182C., by the
method described in Example 7.
Similarly, alkylation of 4,5,6,7-tetrahydrobenzo[b]-
thiophen-4-one with ethyl iodide, propyl iodide, and butyl
iodide affords the corresponding 5-alkyl ketones, which are
converted in the above manner to l-methyl-3-(5-ethyl-4,5,6,7-
tetrahydrobenzo[b]thien-4-yl)urea, 1-methyl-3-(5-propyl~4,5,6,7-
-tetrahydrobenzo[_]thien-4-yl)urea, and 1-methyl-3-(5-butyl-
~0
- 7~ -
~, ,
10~99
-4,5,6,7-tetrahydrobenzo[b]~hien-4-yl)urea, respectively.
EXAMPLE 46
Preparation of l-(methoxymethyl)-3-4,5,6,7-tetrahydrobenzo-
[b]thien-4-yl)urea
In 150 ml. of methanol, 8.24 grams of 4,5,6,7-
-tetrahydrobenzo[b]thien-4-ylurea is stirred and 2.1 grams of
sodium hydroxide pellets followed by 2.31 grams o~ paraform-
aldehyde in 50 ml. of methanol are added. The mixture is
heated at reflux for 10 hoursand cooled to afford crystals
which are collected. The filtrate is evaporated to dryness
and the residue is washed with water to afford 6.7 grams of
solid. Recrystallization of the combined fractions from r
acetone-hexane gives 5.3 grams of 1-(methoxymethyl)-3-(4,5,-
6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 160C.
to 162C.
EXAMPLE 47
Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl thiourea
,,,
A mixture of 13.21 grams of 1-benzoyl-3-(4,5,6,7-
-tetrahydrobenzo[b]thien-4-yl)thiourea in 100 ml. of 10~ sodium
hydroxide solution is heated to reflux for 10 minutes and
cooled. The solid is collected and dissolved in 95~ ethanol
and the solution is evaporated to afford 9 grams of white
solid. Recrystallization of this solid from chloroform/hexane
affords 8.13 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl
thiourea, melting point 129C. to 131C.
EXAMPLE 48
. .= .................................. :
Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea
A sample of 6 grams of 4,5,6,7-tetrahydrobenzo[b]-
thien-4-ylurea is dissolved in 375 ml. of 50~ aqueous acetic
acid and 75 grams of ceric ammonium nitrate is added in por- ~-
tions over a 10 minute period with stirring at 25C. to 35C.
The pale-orange solution is stirred for another 5 minutes and
100 ml. of water is added. The soluti~n is extracted twice
~/
~,~
~1~6~899
with ethyl acetate (450 ml. and 350 ml.) and the combined
extracts are washed with 100 ml. of water. The organic ex-
tract is evaporated to dryness ln vacuo and the brown residue
is crystallized from methanol to afford 2.37 grams of 4,5,6,7-
-tetrahydro-7-oxobenzo[b]thien-4-ylurea, melting point 237C.
to 238C. dec. Recrystallization from methanol affords puri-
~ied product, melting point 245C. to 246C. dec.
Similarly, l-methyl-3-(4,5,6,7-tetrahydro-7-oxo-
benzo[b~thien-4-yl)urea, 1-ethyl-3-(4,5,6,7-tetrahydro-7-oxo-
benzo~_]thien-4-yl)urea, 1-n-hexyl-3-(4,5,6,7-tetrahydro-7-
-oxobenzo[b]thien-4-yl)urea, 1-n-dodecyl-3-(4,5,6,7-tetrahydro-
-7-oxobenzo[b]thien-4-yl)urea, and 1-phenyl-3-(4,5,6,7-tetra- Y
hydro-7-oxobenzo[_]thien-4-ylurea, 4,5,6,7-tetrahydro-4-oxo-
benzo[_]thien-7-ylurea, 1-methyl-3-(4,5,6,7-tetrahydro-4-oxo-
benzo[b]thien-4-yl)urea and the optically active isomers of
4,5,6,7-tetrahydro-7-oxobenzo~_]thien-4-ylureas are pre-
pared by the above procedure starting with the corresponding
ureas.
Substitution of the ceric ammonium nitrate with
silver oxide, chromic anhydride or sodium dichromate also
affords the above mentioned 7-oxo compounds. Chromic an-
hydride in acetic anhydride, followed by hydrolysis, also
affords the 7-oxo compounds. The above-mentioned 7-oxo deri-
vatives are also prepared by oxidixi~g their corresponding
7-hydroxycycloalkano[b]thien-4-ylurea in the same manner.
EXAMPLE 49
Preparation of and separation of 7-hydroxy-4,5,6,7-tetrah~dro-
benzo[b]thien-4-ylurea into the cis -trans isomers
7-Keto-4,5,6,7-tetrahydrobenzo[_-thien-4-ylurea
(0.5 grams, 2.38 mm) is suspended in ethanol (50 ml.) and to
the stirred solution is added solid sodium borohydride (O.5
grams, 13.2 mm). After stirring overnight the mixture is
- treated cautiously with 5% aqueous acetic acid (20 ml.). After
; r., ., _ ,~ _
,s,
~v~9~
stirring 15 minutes the solvent is removed, the residue
dissolved in a small volume of methanol and percolated through
a 1-1/2' x 1-3/4" silica gel dry column eluting with 20~ meth-
anolic methylene chloride. The resulting gum is crystallized
from ethyl acetate/methanol to afford 66 mg. ~13~Y) of the
more polar (L.L.C) alcohol (B), melting point 194C. to 197C.
The mother liquor material i5 separated into its two major
components 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea
by high pressure liquid chromatography on "Spherosil XOA 400"~
(a microporous silica, 5-10 microns) using the solvent sy~tem:
hexane (1800 ml.)/methanol (425)/chloroform (1000~ ~flow rate
13 ml./min.). This procedure affords the less polar al
cohol A ~29 mgs. 6% yield, melting point 162~C. to 169C.
(methanol/ethyl acetate), and the more polar alcohol B (50 mg.,
10% yield~, melting point 197C. to 198C.
EXAMPLE 50
Preparation of 2,4-bis[3'-methylureido]-4,5,6,7-tetrahydro-
enzo~b]thiophene
2-Nitro-4-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
hydrochloride (0.5 grams, 2.13 mmol) is dissolved in concen~
trated hydrochloric acid ~4.3 ml.~. The stirred solu~ion is
treated with stannous chloride dihydrate (2.56 grams,~~ 11.35
mmol) added in portions over a 10 minute period (solution be-
comes hot). The brown solution is stirred for 3 hours, added
to ice/water (20 ml.), made alkaline with 10% sodium hydroxide
and the turbid solution extracted 3 times with methylene
chloride (total volume ~ 100 ml.). The combined methylene
chloride extracts are washed once with brine (20ml.), dried
(sodium sulfate) and evaporated to afford a gum. The gum is
dissolved in methylene chloride (10 ml.) and ether (10 ml.)
and the stirred solution treated with a solution of methyl
isocyanate (0.5 grams, 8.8 mmol) in ether (10 ml.~, added
over a 10-minute period. The mixture is stirred overnight,
~ 63
399
then ~vaporated to dryness and the residue recrystallized
from hot methanol to afford 230 mg. (38% yield) of 2,4-bls-
[3'-methylureido]-4,5,6,7-tetrahydrobenzo[b]thiophene melting
point 233C. to 234Co
EXAMPLE 51
Preparation of 5,6,7,,8-tetrahydro-4~-cyclohepta[_]thien-4-
ylurea
A sample of 5,6,7,8-tetrahydro-4H-cyclohepta[b]-
-thiophen-4-amine hydrochloride is converted to 5,6,7,8-tetra-
hydro-4H-cycloheptaEb]thien-4-ylurea, melting point 217C.
dec., by the method of Example 10.
EXAMPLE 52
Preparation of l-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-
-cyclohepta[b]thien-4-ylurea
By the method described in Example 46, a sample of
5,6,7,8,-tetrahydro-4H-cyclohepta[b]~hien-4-ylurea is converted
to l-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]-
thien-4-ylurea, melting point 197C. to 201C. dec., by the
method described in Example 46.
EXAM2LE 53
Preparation of N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thio-
phen-4-amine
In the manner described in Example 48, N-formyl-
4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is oxidized with
ceric ammonium nitrate to afford N-formyl-4,5,6,7-tetrahydro-
-7-oxobenzo[b]thiophen-4-amine, melting point 118C. to 120C.
dec.; this product is extracted from the reaction mixture
with methylene chloride. The use of chromic .anhydride in
acetic anhydride followed by hydrolysis also affords the
identical produc~.
~ 65~
89
EXAMPLE 54
Preparation of 4,5,6,7-tetrahydxo-7-oxobenzo[b]thiophen-4-
-amine hydrochloride
In the manner described in Example 36, N-formyl-
4,5,6,7-tetrahydro-7-oxobenzo[b~thiophen-4-amine is hydrolyzed
with 2N hydrochloric acid/ethanol to afford 4,5,6,7-tetrahydro-
-7-oxobenzo[b]thiophen-4-amine hydrochloride, melting point
230C. to 232C. dec. F
EXAMPLE 55
Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[_]thien-4-yl
isocyanate and urea
.
Conversion of 4,5,6,7-tetrahydro-7-oxobenzo[_]thio- v
phen-4-amine hydrochloride to 4,5,6,7-tetrahydro-7-oxobenzo-
[b]thien-4-yl isocyanate is accomplished by heating a toluene
mixture of the hydrochloride at reflux temperature while
phosgene is introduced. After the mixture becomes less cloudy,
it is cooled and filtered. Evaporation of the filtrate affords
the crude 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl iso-
cyanate; IR maximum = 2250 cm 1,
Addition of N~3/MeOh solution to this isocyanate
affords 4,5,6,7-tetrahydro-7-oxobenzo[_]thien-4-ylurea.
EXAMPLE 56
The following compounds are prepared by allowing
4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride
to react with RNCX in the presence of an equimolar quantity
of triethylamine in solvents such as aromatic solvents, chlor~
inated hydrocarbons, ethers, lower alkyl Cl-C4 ketones, or
mixtures thereof.
~ ~,
L~ ~
~ Gs-
.
10608g9
RNCX R PrOduct X
CH3NCO CH3-
C2H5NC C2H5 0
CC13C-NCO
0 C13C-C- o
C6H5CH2NCO C6H5CH2- 0
C2H5NCS C2H5-- S
' C~30--CH2NCO CH3--0-CH2- o
CH30--'CH'2NCS CH3--0-CH2-- S
CH30 ~ NCO CH~ ~ O
EXAMPLE 57
The following compounds are prepared by reacting
4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate to
react with the appropriate amines in inert solvents, as
described before in Example 35.
~ ~R
NH-C-N
~- ~ R2
S
O
F
' ~'1 _;43 _
. ~.......... , . _ ___ _ . ... ..... _ ___ _ . _. _
~6C~89~
Product
-Amines Rl R2
.
NH2 OCH H -OCH3
NH2 OH H -OH
CH3NH-OH -CH3 ~
CH3NH-OCH3 -CH3 -OCH3
CH2=CH-CH2-NH2 H -CH2-CH=CH2 r
CH_C-CH2-NH2 H -CH2-C_CH
tCH3)2N~ -CH3 -CH3
C6HsCH2NH2 H -CH2-C6H5
C2H5NH2 H -C2H5
n C4HgNH2 n-C4Hg
O O
~H3C-NH2 ~ C CH3
15 ~ CX2-NH2 H -CH
2 NH2 H CH
CH3
CH-NH2 H -CH(CH3)2
., ~
CH3
EXA~.PLE 58
By the method described in Example 49, the fol.lowing
compounds are prepared as cis and trans mixtures from their
corresponding keto precursors:
Optically active isomers of 7-hydroxy-4,5,6,7-
-tetrahydrobenzo[b]thien-4-ylurea, 1-methyl-3-(7-hydroxy- t
-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-ethyl-3-(7-hydroxy-
-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1,1-dimethyl-3-
-(7-hydroxy-4,5,6,7-tetrahydrbenzo[b]thien-4-yl)urea, l-methoxy-
-3-(7-hydroxy-4,5~6,7-tetrahydrobenzo[b]thien-4-yl)urea,
l-methyl-l-methoxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[_]-
~ _
D-i ~7
.. . . .
.. ,__ , .... . . , ,__
~6~ 39
thien-4-yl)rea, 1-hydroxy-3-(7-hydroxy-4,5,6,7-tetrahydro-
benzo[b]thien-4-yl)urea, 1-hydroxy-1-methyl-3-(7-hydroxy-
-4,5,6/7-tetrahydrobenzo[b]thien-4-yl)urea, l-methoxymethyl-
-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,
1-allyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)--
-urea, 1-~2-propynyl)-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo-
[b]thien-4-yl)urea, 5,6,7,8-tetrahydro-4H-8-hydroxycyclohepta-
~b]thien-4-ylurea, 4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-
-7-ylurea.
EXAMPLE 59
Preparation of 5,6,7,8-tetrahydro-4H-8-oxocyclohepta[b]thien-
-4-ylurea
A sample of 5,6,7,8-tetrahydro-4H-cyclohepta[b]-
thien-4-ylurea is oxidized with ceric ammonium nitrate in the
manner described in Example 48 to afford 5,6,7,8-tetrahydro-
-4~-8-oxocyclopheta[b]thien-4-ylurea, melting point 246C. to
2.48C. dec.
EXAMPLE 60 r~
Preparation of 1,2-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
.
-4-yl _ thiopseudourea
In 100 ml. of methanol, 2.3 ml. of methyl iodide
and 7.1 grams of 1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
-4-yl)thiourea is stirred at room temperature for 4 days. The
solvent is evaporated ln vacuo and the residual oil is heated
and stirred in ethyl acetate to afford crystals~ The crystals p
are collected and recrystallized from chloroform/hexane and
then from chloroform/benzene to afford 2.5 grams, melting
point 145C! to 148C., and 6.53 grams, melting point 143C.
to 145C., of 1,2-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-
-4-yl)-2-thiopseudourea hydroiodide.
Similar-ly, the hydrochloride and hydrobromide
salts are prepared by using methyl chloride and methyl bromide,
respectively.
,fi ~ &
.... . . . .. .... . .. .
~ - .
- - -
1~6~)899
Substitution of l-butyl-3-(4,5,6,7-tetrahydrobenzo-
lb~thien-4-yl)thiourea in the above example affords 1-butyl-2-
-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-2-thiopseudo-
urea hydroiodide, melting point 131C. to 133C.
EXAMPLE 6_
Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl guanidine
hydrochloride
In 100 ml. of n-butanol, 8.2 grams of 4,5,6,7-tetra-
hydrobenzo[b]thiophen amine hydrochloride and 5 grams of
cyanamide are heated at reflux temperature for 30 hours and
10 minutes. The solvent is then removed by vacuum distillation
and the residual oil is stirred with acetone. The acetone
mixture is filtered and the filtrate evaporated to dryness
in vacuo to afford an oil. The oil is washed with ether
several times and again treated with acetone to afford a white
solid. This solid is coilected and washed with acetone to
afford 5.5 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl
guanidine hydrochloride, melting point 212C. to 214C.
Example 62
Preparation of 5-keto-4,5,6,7 tetrahydrobenzo[b]thiophene
6,7-Dihydrobenzo[_~thiophene (3.3 grams, 24.3 mmol~
is dissolved in methylene chloride (250 ml.) and the solution
is cooled to - -25C. and solid 85~ _-chloroperbenzoic acid
(6.19 grams, 30.5 mmol) is added with shaking. The mixture
is allowed to stand in the refrigerator (3-7C.) for 3 days.
The solution is washed with saturated sodium bicarbonate
(3 x 100 ml.) and water (100 ml.), and dried over sodium sul-
fate. It is then evaporated to afford a brown semi-solid which
is assumed to be a mixture of epimeric hydroxy-m-chloroben-
zoates (589 yrams, 79~ yield); a ma] 3500~ 1730 cm 1
The mixture of hydroxy-_-chloroben~oates (5.89 grams,
19.1 mmol) is refluxed for one hour with 95% ethanol (160 ml.)
and 20% sulfuric acid (160 ml.). The bulk of the ethanol is
~? -~-
~a~60~il9~
removed in vacuo and the solution extracted three times with
methylene chloride (3 x 150 ml.). The extracts are combined
and washed with saturated sodium bicarbonate (2 x 150 ml.),
brine (150 ml.), dried (Na2SO4) and evaporated to afford a
gum (3.8 grams). The gum is chromatographed on a dry column
(SiO2 3' x 1 3/4") (methylene chloride eluent) to furnish the
required ketone as a light brown oil (0.95 gram, 33% yield,
neat 1725).
max
EXAMæLE 63
Preparation of l-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-5-
-yl)urea
5-Keto-4,5,6,7-tetrahydrobenzo[b]thiophene (0.95
grams, 6.25 mmol) is stirred overnight at room temperature
with ethanol (10 ml.), methoxyamine hydrochloride (1.05 grams,
V-12.6 mmol) and 10~ sodium hydroxide (2.5 ml. 6.25 mmol).
Saturated sodium bicarbonate (25 ml.) is added and the ethanol
is removed in vacuo. The residual solution is extracted twice
with methylene chloride (total volume 75 ml.) and the methylene
chloride layers combined, washed with water (25 ml.), dried
(sodium sulfate), and evaporated to afford the methoxime
as a brown oil (1.06 grams, 94~ yield); ~ maxt 1650 (weak) 1060.
The crude methoxime (1.06 grams, 5.85 mmol) is stir-
red with tetrahydrofuran (7 ml.). The cooled mixture is
treated with borane THF (15 ml., 15 mmol) (temperature kept
below 10C.). The mixture is refluxed for 4 hours, cooled to
15C., and water (1 ml.) is added, followed by 20% potassium
hydroxide (10 ml.). After refluxing for one hour, the THF t
is removed in vacuo and the residue extracted twice with
methylene chloride(total volume 100 ml.). The extracts are -
combined, washed brine (20 ml.), dried (Na2SO4)j and evaporated
to afford a colorless oil (700 mg.). The oil dissolved in
ether (10 ml.) and treated with a solution of methyl isocya-
7o
1~6~)~9~
nate (0.7 gram, 12.3 mmol) in ether (10 ml.). The mixture is
stirred overnight and filtered. The cake is washed with ether
~5 ml.) and air-dried to afford the title compound as a white
solid (430 mg., 35% yield), me:Lting poing 154-158C. Re
crystallization from aqueous methanol affords the analytical
specimen, melting point 167-169C.
Similarly, when methyl isocyanate is replaced with
ethyl isocyanate, n-hexyl isocyanate, dimethylcarbamoyl
chloride, or allyl isothiocyanate, l-ethyl, l-(_-hexyl),
and 1,1-dimethyl-3-~4,5,6,7-tetrahydrobenzo[b]thien-5-yl)ureas,
and l-allyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-5-yl~thiourea
are obtained.
EXAMPLE 63
A sample of 6,7-dihydrobenzo[_]thiophene is stirred
in the cold in 96% sulfuric acid containing 4-6 mole equiva-
lents of urea. After 1 hour the mixture is poured on ice and r
the organic phase is removed. Evaporation of the organic phase
to dryness ln vacuo affords 4,5,6,7-tetrahydrobenzo[b]thien-
-- -4-ylurea.
EXA~LE 64
A 1 gram sample of 4-hydroxy-4,5,6,7-tetrahydro-
benzo[b]thiophene is stirred in the cold for several hours in
thionyl chloride (5 ml.) and the mixture is evaporated to
dryness. The crude 4-chloro-4,5,6,7-tetrahydrobenzo[b]thio-
phene is then added to a mixture of urea (1-5 mole-equivalents)
in dimethylformamide and diisopropyl ethylamine. The mixture
is warmed, after several hours, to 50C. and after 4 hours is
poured on ice and the product, 4,5,6,7-tetrahydrobenzo[b]thien-
-4-ylurea, is collected by filtration.
EXAMPLE 65
A sample of 6,7-dihydrobenzo[b]thiophene is stirred
with silver isocyanate and iodlne as described in Example 40
and the resulting product, 5-iodo-4,5,6,7-tetrahydrobenzo[_]-
_~ _
~ ~ !
- 1~6~il899
thien-4-yl isocyanate is treated with concentrated ammonia
solution to afford 5-iodo-4,5,6,7-tetrahydrobenzo[_~thien~4-
-ylurea. This latter product is then reduced in the manner
described in Example 41 to afford 4,5,6,7-tetrahydrobenzo[b]-
thien-4-ylurea.
The following products are also obtained by reacting
5-iodo-4,5,6,7-tetrahydrobenzo[_3thien-4-yl isocyanate with
R2R3NH to afford the corresponding iodo ureas, which are then
hydrogenated in the above manner to give compo~mds of the
formula: R
NH-CO-N ~ 2
~ ~3
lS R2 3
H -CH3
H -C2H5 r
H -CHtCH3)2
- -CH3 -CH3 1-
H -OH
H -OCH3
-CH3 -OH
-CH3 -OCH3
!
When allyl amine and 2-propynyl amine are used to
give l-allyl or 1-(2-propynyl)-3(5-iodo-4,5,6,7-tetrahydroben-
zolb]thien-4-yl)urea, the resulting iodo ureas are deiodinated
with tributyl tin hydride (Bu3SnH). This reducing agent
(Bu3SnH) can also be used to deiodinate these aforementioned
iodo ureas, while use of Zn/HCl to give the desired ureas and
polymeric material.
'7
