Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
21
Field of the Invention
This invention relates to 2-imino substituted
isothioureidobenzenes, to processes for making such
compounds, to methods of treating helminth and fungus
in~ections and to anthelmintic and antifungal compositions
containing them.
Description of the Invention
British Pat. Nos. 1,214,415 and 1,307,250; U.S.
Pat. Nos. 3,958,008; 3,860,586 and 3,836,569 and
Netherlands Pæt. No. 7,401,787 disclose numerous thio-
ureas useful as anthelmintics, though none have a sub-
stituent on the sulfur. German Pat. No. 2,303,048
discloses 2-acylated amino-S-substituted isothioureido-
benzenes as anthelmintics. However, there are no
re~erences disclosing compounds having both an imino
substituent on the benzene ring and a substituted sulfur
atom in the thioureido group. Other patents disclosing
anthelmintic compounds include U. S. Pat. Nos. 3,865,948
and 4,00~,217; also, British Pat. No. 1,350,277.
An ob~ect of this invention is to provide a new
class of 2-imino substituted isothioureidobenzenes (I,
infra), methods for preparing these compounds, compositions
containing said compounds and to their use as anthelmintic
and antifungal agents.
The novel 2-imino substituted isothioureidobenzenes
(I, infra) of this invention nave the following struct~ral
formula:
'~'
* - 2 -
76-78A
521
x
~=CIIR2
o
=N-C-OR
SR
I
wllerein R is alkyl, for example, lower alkyl of from l
to 8 carbon atoms such as methyl, ethyl, n-propyl, n-
butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl,
octyl and the like; alkenyl, for example, lower alkenyl
of from 3 to 8 carbon atoms such as propenyl, butenyl,
pentenyl, hexenyl, heptenyl, octenyl and the like;
alkynyl, for example, lower alkynyl of from 3 to 8
carbon atoms such as propynyl, butynyl, pentynyl, hexynyl,
heptynyl, octynyl and the like; polynuclear aralkyl su~h
as napthylmethyl, napthylethyl, phenanthrenyimethyl and
the like; mononuclear aralkyl such as benzyl, phenethyl,
phenylpropyl and the like which may be ring-substit~lted
with from l to 3 groups such as halo, alkyl, alkoxy,
nitro, cyano and the like; mononuclear aryloxy lower
alkyl, for example, phenoxy lower alkyl of from 3 to 6
carbon atoms in the a]kyl group including phenoxypropyl,
phenoxybutyl, phenoxypentyl, phenoxyhexyl and the like~
cycloalkylalkyl, for example, cycloalkyl lower alkyl of
from 5 to 6 nuclea~ carbon atoms su^h as cyclopentylmethyl,
cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and
the like; cyano lower alkyl of from 3 to 6 carbon atoms
such as cyanopropyl, cyanobutyl, cyanopenlyl, cyanohexyl
76-78A
110~521
and the like; hydroxy lower alkyl of from 3 to 8 carbon
atoms such as hydroxypropyl, hydroxybutyl, hydroxypentyl,
hydroxyoctyl and the like; aralkenyl, for example, poly-
and mononuclear aralkenyl such as phen~lpropenyl and the
like; alkoxyalkyl, for example, lower alkoxy lower alkyl,
such as methoxypropyl, ethoxypropyl, ~ethoxybutyl, propoxy-
butyl and the like; alkoxycarbonylalkyl, for example,
lower alkoxycarbonyl lower alkyl wherein lower alkyl has
3 to 6 carbon atoms, such as methoxycarbonylpropyl,
ethoxycarbonylbutyl, ethoxycarbonylpentyl, propoxycarbonyl-
hexyl and the like; phthalimido lower alkyl such as
phthalimidobutyl and the like or phenoxycarbonylalkyl,
for example, phenoxycarbonyl lower alkyl of from 3 to 6
carbon atoms such as phenoxycarbonyl propyl, phenoxycarbonyl
butyl, phenoxycarbonylpentyl, phenoxycarbonylhexyl and
the like; R is alkyl, for example, lower alkyl of from
1 to 6 carbon atoms such as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl
and the like or lower alkoxyalkyl such as methoxyethyl
ethoxyethyl, propoxyethyl and the like; R2 is alkyl, for
example, lower alkyl of from 1 to 6 carbon atoms; substi-
tuted or unsubstituted aryl, of from 4 to 6 nuclear
carbon atoms, for example, mononuclear aryl of from 4 to
6 nuclear carbon atoms, polynuclear aryl of from 10 to 14
carbon atoms, heteroaryl of from 5 to 6 nuclear atoms
containing from 1 to 3 heteroatoms selected from oxygen,
nitrogen or sulfur, examples of aryl include phenyl,
naphthyl, thienyl, pyridyl, furyl, furylmethyl, pyrroli-
dinyl, pyrrolyl, isothiazolyl, oxadiazolyl, thiadia.zolyl,
3o
76-78A
llQC;~5Z~
imidazolyl,isooxazolyl, N-methylpyrryl, oxazolyl, pyrimidyl,
and the like which may be unsubstituted or substituted with
from I to 3 radicals selected from halo, such as chloro,
bromo and the like, lower alkyl having from I to 5 carbon
76-78A
110~5~1
atoms, lower alkoxy having from l to 5 carbon atoms;
di-lower alkylamino such as dimethylamino and the like,
lower alkanoylamino of from l to 5 carbon atoms; phenoxy,
benzyloxy, 3,4-lower alkylenedioxyphenyl, phenylthio lower
alkyl, cyano, nitro, alkylthio or arylthio and 'he li'.e;
and X is hydrogen, nitro, halo, such as chloro,iodo, bromo
fluoro and the like; lower alkanoyl of from 2 to 5
carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl
and the like; lower alkyl of from 1 to 4 carbon atoms such
as methyl, ethyl, propyl, _-butyl and the like; lower
alkoxy, such as methoxy, ethoxy, propoxy, butoxy, pentoxy
and the like; thiocyanato, a radical of the formula:
Y-S(O)n wherein Y is lower alkyl of from l to 5 carbon
atoms; lower alkenyl (C3-C6), lower alkynyl (C3-C6),
cyclo lower alkyl (C3-C7), a 5- or 6-membered heterocycle,
such a pyridyl, thienyl, furyl, oyrimidyl, thiazolyl
and the like or mononuclear aryl such as ohenyl and n is
an integer of O to 3, X is also lower alkylcar~on~llamino,
such as methylcarbonylamino ~nd the like, lower (Cl-C~)
2~ alkoxy carbonylamino such as methoxycarbonylarino,
isopropoxycarbonylamino and the like, a 5- or 6-membered
cycloalkylcarbonylamino such as cyclopentylcarbonylamino,
cyclohexylcarbonylamino and the like; a radical of the
formula: Y'~- wherein Y' is mononuclear aryl such as
phenyl and the like; cyclo lower alkyl (C3-C7), a 5- or
6-membered heterocycle, such as oyridyl, 2-thienyl, furyl
and the like or X is also a radical of the formula: Y"O-
wherein Y" is lower alkyl (Cl-C5), mononuclear aryl, such
as phenyl and the like, lower alkenyl, mononuclear arylkyl
or a 5- or 6 membered heterocycle and, when substituted,
the substituents on
76-78
S21
the Y, Y' and Y" are selected from halo, cyano, lower
alkyl, lower alkoxy, lower alkanoyl, lower alkylthio,
lower alkylsulfinyl, lower alkylsulfonyl, phenylthio,
phenylsulfinyl, phenylsulfonyl, phenoxy, halophenoxy,
benzyloxy, trifluoromethyl or carbo lower alkoxy and
the nontoxic, pharmaceutically or agronomically acceptable
acid addition salts such as those formed with acids such
as hydrochloric, sulfuric, nitric, phosphoric, acetic,
citric, benzoic, lactic and the like and amides of the
ester such as amino, mono- and di-lower alkylamino and
the like. Representative R2 radicals include chloro-
phenyl, bromophenyl, methylphenyl, ethylphenyl, butylphenyl,
pentylphenyl; 2,~-dichlorophenyl; 3,4~dichlorophenyl;
methoxyphenyl, ethoxyphenyl, dimethylaminophenyl, acetamido;
3,4-methylenedioxyphenyl, methylthiophenyl, phenylthio- !
phenyl and the like.
When compounds of general Formula I can exist in
various isomer and stereoisomer forms, all such isomers
and their mixtures and racemates are included within the
scope of the present invention.
Preferred Embodiment
A preferred embodiment of this invention relates
to the 2-imino substituted isothioureidobenzenes (Ia,
infra) of the following structural formula:
xl
~5 ~ N=CHR5
~ O
\NHIC=NC-OR4
SR3
I a
76-78A
~O~S2~
wherein R3 is lower alkyl, lower alkenyl, lower alkynyl,
benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl lower
alkyl of from 5 to 6 nuclear atoms, phenoxy lower alkyl
of from 3 ~o 6 carbon atoms, cyano lower alkyl of from 3
to 6 carbon atoms, lower alkoxy carbonyl lower alkyl
wherein lower means from 3 to 6 carbon atoms, phthalimido
lower alkyl, phenyl lower alkenyl of from 3 to 6 carbon
atoms or hydroxy lower alkyl; R4 is lower alkyl; R5 is
mononuclear aryl of from 4 to 6 nuclear carbon atoms, poly-
nuclear aryl of from lO to 14 nuclear carbon atoms or
heteroaryl of from 5 to 6 nuclear atoms containing from 1
to 3 hetero atoms such as o, m, or p-nitrophenyl, o, m
or p-dimethylaminophenyl, lower o, m or _-alkoxyphenyl,
o, m or _-cyanophenyl, o, m or p-acetamidophenyl, methyene-
dioxyphenyl, phenyl, 2-furyl, 5-methyl-2-furyl, 2-thienyl,
o, m, or p-halophenyl, lower _, m or _-alkyl phenyl or
dihalophenyl and Xl is in the 4 or 5 position of the
benzene ring and is selected from hydrogen, lower alkyl
carbonylamino, lower alkoxycarbonylamino, lower alkoxy,
lower alkanoyl, propylthio, propylsulfinyl, propylsulfonyl,
propylsulfonyloxy, propoxysulfonyl, phenylthio, phenyl-
sulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy
or benzoyl. ~specially preferred are those compounds
wherein Xl is hydrogen, 4-benzoyl, 5-propylthio or
5-phenylthio. These compounds exhibit particularly good
anthelmintic and antifungal activity.
The produc~s may be prepared by several alter-
native processes including treating a 2-imino substituted
thioureidobenzene with a base and an organic halide, a
diester of sulfuric acid or diester of sulfurous acid or
by treating a 2-amino substituted isothioureidobenzene
w~h an aldehyde.
76-78A
5Zl
The first method for preparing the 2-imîno sub-
stltuted iso~hioureidobenzenes (I, supra
~/
.. ..
ll()~S21
invention comprises treating the corresponding 2-imino
substituted thloureidobenzene (II, infra) with a base,
for example, an alkali metal or alkaline earth metal base,
such as sodium hydride, calcium hydride, sodium hydroxide,
pota~sium hydroxide, calcium hydroxide, potassium carbonate
and the like followed by treatment with either an organic
halide, a diester of sulfuric acid or diester of sulfurous
acid. The reaction may be conducted at a temperature in
the range of from -10C. to about 60C. for a period of
time of from a few minutes to about 24 hours. Any solvent
in which the reactants are reasonably soluble and sub-
stantially inert may be employed. Suitable solvents
include dimethylformamide, acetone, 1,2-dimethoxyethane,
dimethyl sul~oxide and the like. The following equation
illustrates this process:
N=CHR2 ~ Base ~ ~ ; N=CHR2
01 ~ 11
H-CNHC-ORl or RS04R H-f=NCOR
S SR
II I
wherein R, Rl and X are as defined above and x2 is halo
such as chloro, bromo or iodo.
A second method for preparing the compounds of
Formula I comprises kreating 2-amino substituted iso-
thioureidobenzene with an aldehyde (R2CHQ) in a manner
similar to that described below for the
- 10 -
.~.'
. ~,~,,,
76-78
11(3~5~ ~
prepara~ion of the compounds of Formula III. ~he
following equation illustrates this process:
~IC=NCOR
SR
IIa
wherein R, Rl, R2 and X are as defined above.
The compounds of Formula II are either
known compo~nds or may b~e prepared by treating an
appropriately substituted l-imin3-2-aminobenzene (III,
infra) with a carboalkoxyisothiocyanate (IV, infra),
to afford the desired compounds of Formula II. The
following equation illustrates this process:
X X
N=CHR2 + S=C=NC-ORl ~ ~N=C,-~o[R2
2 NHCNHC3R
S
III IV II
wherein Rl, R2 and X are as defined above. This reaction
is conveniently conducted in a suitable inert solvent such
as diethyl ether, acetone, and the like for a period of
time of from ~O minutes 'o 6 ~ours.
76-78l~
ll~CtS~
We have found that the co~pounds of
Formula II, supra, wllich have been disclosed as
~nthelmintics are also useful as fungicides.
Compound IIa is prepared by the reaction
O
of a thioureidobenzene (V, infra) where Z-C-NHC-ORl
with RX2, RS03R or RSO~R under the sa.~e conditions as
described in the preparation of Formula I from ~ormula II.
~ he compounds of Formula II and also
the compo m ds of Formula IIIa, l-substituted-i~in~-2-
substituted aminobenzene, may be prepared by treating thecorrespondingly substituted isothioureidobenzene or
substituted 1,2-diaminobenzen~ ~V, infra), respectively,
with an aldehyde. The following equation illustrates this
~rocess:
~ N~2 + a2c~o ~ ~ ~I=c~a2
N~-Z' NH-Z'
V IIIa
wherein R2 and X are as defined above anl Z' is hydrogen
or
o
-C -NHC -O
whereln R is as defined above~ ~his rea^tion is
2 generally conducted at a temperatllre in the range of
from about 0C. to about 11C. for a period of time of
l~lU~521
from one mi.lute to about 24 hours. ~uitab~ solvenls
~ich can be employed include aceton~, methanol, ethanol,
.. .. *
iso-propanol, methylC~llosolve,dimethylformamide, di-
met~yl sulfoxide and the like. An acid catalyst such
as P-toluene sul~onic acid, sulfuric acid and the like
may be employed. L~y water formed dur~ng the reaction
may be removed by azeotropic distillation.
When X is the radical Y~, the sulfinyl
~i.e.,Y-~0-) and the sulfonyl product can be prepared by
1~ treating said YS substituted compound with one or two
e~uivalents of an oxidizing agent, respectively. ~he
oxidizing agen' may be m-chloroperbenzoic acid, perbenzoic
acid, peracetic acid, sodium 'nypochlorite and the like.
~he reaction is conducted at a temperat~L~e in the range
of from -20C~ to 50C. for a period of time o~ from
about 5 minutes ~o 24 houL~s. Any substantially inert
solvent in which the reactants are reasonably soluble may
be employed including methylene dichloride, chloroform,
carbon tetrachloride, banzene,toluene, chlorobenzene,
acetone and the like.
The thioureidobenzene of Formula
S O
(Z'C-~C ORl) is prepared by t~eatin, a 1,2-diaminobenzene
derivative or l-amino-2-nitrobenzene derivative with a
carboalkoxy isothiocyanate in the man~er described above
and l~hen a nitrobenzene reducing said nitro to an amino
~roup by reduction methods well-known to those skilled
in ths art.
*Trademark. Methyl "Cellosolve" i5 ethylene glycol
monomethyl ether.
13
7~-78
SZl
2-I-mino substituted isothioureidobenzenes
of Formula I are anthelmintics and have br3ad spectrum
activity against parasites of animals, especially warm
blooded animals, including both mature and im~ature
parasitic forms. In particular, these compolmds exhibit
high ac~ivity against various helmintic infectiors of the
intestinal tract of economically important animals, coupled
with low systemic toxicity to the host animal.
For exanple 7 the disclosed compounds are
generally effective in clearing mice of worm infections,
for laboratory purposes, including: Syphacia obvelata and
As~icularis tetraPtera~ the migratory stages of Ascaris
suum, H menole~sis nana and Nematospiroides dubius.
Compounds of Formula I have been
demonstrated as efficacious against gastrointestinal
parasites in sheep, such as Moniezia spP, Haemonchus
contortus, Ost,erta~ sP~, lrichost~on~lus s~p,
Nematodirus sPP, Tri^huris ovis, Cooperia spp, Capillaria
s~, Stron~Yloids Pa~_llosus, BunostomlIm tri,~oncephalum and
20 OesoPha~3stomum spp. lhe compounds are active against lung
wo~ms in ruminants especially Dictyocaullls filaria, in
sh~ep and Dict~ocaulus viviparus and in cattle. lhe
co~pounds (I) may alsoke used in treating Fasciola
~i~antica in cat51e. In addition, the compounds are
2~ effective against liver flukes (Fasciola ha~atica) in
sheep and cattle.
~ nimals of low weigh~ are t~ea5ed with
m~t doses ranging no higher than a few milligrams;
whereas, animals of high body weigh5, such as ruminants,
- 14 -
?o-78 i~5
521
require proportionately lar~er ~nit doses ranging up to
several grams. Preferably, a single dose is administered
for each anlmal species based on the weight of that species.
The amount of ingredient administered
will depend on the weight of the host and will usually
be a unit dosage between about 1 mg./kg. and 125 mg./kg.
of body weight. It is ^ontemplated that dosage units
containing the compounds of Formula I of this invention
as the essential active ingredienl will be administered,
10 orally or by injection, in the treatment and control of
helminti^ infections in man and do~estic animals such as
sheep, cat~le, horses, dogs, cats, fish, swine and goats.
Further, applicants have found hat
the compounds of Formula I and Formula II of this inven'ion
15 display broad spectrum antifungal activity. It is con-
templated, therefore, that an.ifungal compositions con-
taining these compounds as an essential active ingredient
will be employed in controlling the growth of fungi in or
on animals and plants as well as in the paint, wood,
20 textile, cosmetic, leather, tobacco, fur, rope, paper,
pulp, plastic, fuel, rubber and food industries.
~ en used as an anthelmintic agent for
the treatment and/or prevention of helminthiasis, the
novel compounds o~ Formula I of this invention may be
25 administered orally, rectally, intranasally, sublingually
or topically, in a unit dosage form ,uch as a capsule,
bolus, tablet, suppository, paste, gel, spray, powder,
ointment, cream or as a liquid drench. ~hey may also be
administered orally by intimatel~ dispersing them in an
7~-7
`SZl
animal feedstuff or by using them as a top dressing or
in the form of pellets which are added to a finished
feed. Alternatively, they may be administered to animals
in a liquid carrier vehicle by intraruminal, interamuscular
and intratracheal injection. In addition, polymeric im-
plants providing a controlled release rate can be employed
for administration. The quantity of active material re-
quired to give the best anthelmintic response will depend
upon the particular compound employed, the species of
animal to be treated and the type and severity of hel-
minth infection. Good results are usually obtained when
there is administered a total dose of from about 5 to
about 125 mg. of active ingredient per kg. of animal
body weight. Such total dose may be given at one time or
in divided doses over a short period of time such as 1
to 3 days.
The 2-imino substituted isothioureidobenzenes and
acid addition salts and metal salt complexes of the
present invention are useful as agricultural fungicides
and can be applied to various loci such as the seed, the
soil or the foliage. The compounds can be employed in
technical or pure form or in solutions or in formulations.
The compounds are usually taken up in an agronomically
acceptable carrier or are formulated to render them
suitable for use as fungicides. For example, the com-
pounds can be formulated as wettable powders, emulsifiable
concentrates, dusts, granular formulations, aerosols, or
flowable emulsion concentrates. In such formulations,
the compounds are usually extended with an agronomically
S21
acceptable liquid or solid carrier and, when desired,
suitable surfactants are also incorporated.
By the term "agronomically acceptable carrier" is
meant any substance which can be utilized to dissolve,
disperse, or diffuse the compounds without impairing
the effectiveness of the compound and which is environ-
mentally acceptable.
It is usually desirable, particularly in the case
of foliar spray formulations, to include adjuvants, such
as wetting agents, spreading agents, dispersing agents,
stickers, adhesives and the like in accordance with the
agricultural practices. Such adjuvants commonly used in
the art can be found in the John W. McCutcheon, Inc.
publication "Detergents and Emulsifiers, Annual."
In general, the compounds of this invention can
be dissolved in organic solvents such as acetone, methanol,
ethanol, dime~hylformamide, pyridine, dimethyl sulfoxide
and the like and the resulting solutions can be extended
with water. The concentrations of the solution can vary
from about 1% to about 90% with a preferred range being
from about 5% to about 50%.
For the preparation of emulsifiable concentrates,
the compound can be dissolved in suitable organic solvents,
or a mixture of solvents, together with an emulsifying
agent which permits dispersion of the fungicide in water.
The concentration of the active ingredient in emulsifiable
concentrates is usually from about lOæ to about 90~ and in
flowable emulsion concentratesg can be as high as about 75,0.
Wettable powders suitable for spraying, can be
-17
7~ -7!~A
S21
prepared by admixing the compounds with a finely divided
solid, such as clays, inorganic silicates and carbonates,
and silicas and incorporating wetting agents, sticking
agents, and/or dispersing agents. The concentration of
active ingredients in these formulations is usually in
the range of from about 20% to about 98%, preferably
from about 40% to about 75%. A typical wettable powder
is made by blending 50 parts of 1-imino(2-furylmethyl)-2-
(3-carbomethoxy-S-buty]isothioureido)benzene~ 45 parts
of a synthetic precipitated hydrated silicon dioxide
sold under the trademark Hi-Sil ~, and 5 parts of sodium
lignosulfonate. In another preparation a kaolin type
(Barden) clay is used in place of the Hi-Sil wettable
powder, and in another preparation 25% of the Hi-Sil is
replaced with a synthetic sodium silico aluminate sold
under the trademar~ Zeolex ~ 7.
Dusts are prepared by mixing the compounds with
finely divided inert organic or inorganic solids.
Materials useful for this purpose include botanical flours,
silicas, silicates, carbonates and clays. One convenient
method of preparing a dust is to dilute a wettable
powder with a finely divided carrier. Dust concentrates
containing from about 20% to about 80% of the active
ingredient are commonly made and are subsequently diluted
to from about 1% to about 10~ use concentration.
The compounds of this invention can be applied as
fungicidal sprays by methods commonly employed, such as
conventional high-gallcnage hydraulic sprays, low-
gallonage sprays, air-blast sprays, aerial sprays and
- 18 -
7(~- 7 ~
21
dusts. ~he dilution and rate of application will depend
upon the type of equipment employed, the method of appli-
cation and diseases to be controlled, but the preferred
effective amount is usually from about 0.1 lb. to about
50 lbs. per acre of the active ingredient.
As a seed protectant, the amount of fungicide
coated on the seed is usually at a dosage rate of from
about 0.1 to about 20 ounces per hundred pounds of seed.
As a soil fungicide the compound can be incorporated in
the soil or applied to the surface usually at a rate of
from about 0.1 to about 50 lbs. per acre. As a foliar
fungicide, the compound is usually applied to growing
plants at a rate of from about 0.25 to about 10 lbs. per
acre.
Fungicides which can be combined with the fungicides
of this invention include:
(a) dithiocarbamate and derivatives such as:
ferric dimethyldithiocarbamate (ferbam),
zinc dimethyldithiocarbamate (ziram),
manganese ethylenebisdithiocarbamate (maneb)
and its coordination product-with zinc ion
(mancozeb), zinc ethylenebisdithiocarbamate
(zineb), zinc propylenebisdithiocarbamate
(propineb), sodium methyldithiocarbamate
(metham), tetramethylthiuram disulfide
(thiram), the complex of zineb and polyethylene
thiuram disulfide, 3,5-dimethyl-1,3,5-2H-tetra-
hydrothiadiazine-2-thione (dazomet); and mix-
tures of these and mixtures with copper salts;
-- 19
- ~G-)X
11(J~521
(b) nitrophenol derivatives such as:
dinitro~ methylheptyl)phenyl crotonate
(dinocap), 2-sec-butyl-4,6-dinitrophenyl-3,3-
dimethylacrylate (binapacryl), and 2-sec-butyl-
4,6-dinitrophenylisopropyl carbonate;
(c) Heterocyclic compounds such as N-trichloro-
methylthiotetrahydrophthalimide (captan), N-
trichloromethylthiophthalimide (folpet), 2-
heptadecyl 2-imidazole acetate (glyodine), 2-
octylisothiazol-3-one, 2,4-dichloro-6-(o-chloro-
anilino)-s-triazine, diethyl phthalimidophosphoro-
thioate, 4-butyl-1,2,4-triazole,5-amino-1-[bis-
(dimethylamino)-phosphinyl]-3-phenyl-1,2,4-
triazole, 5-ethoxy-3-trichloromethyl 1,2,4-
triadiazole, 2,3-dicyano-1,4-dithiaanthraquinone
(dithianon), 2-thio-1,3-dithio-[4,5-b] quin-
oxaline (thioquinox), methyl l-(butylcarbamoyl)~
2-benzimidazole carbamate (benomyl, 2-(4'-
thiazolyl)benzimidazole (thiabendazole), 4-
(2-chlorophenylhydrazone)-3-methyl-5-isoxa-
zolone, pyridine-2-thio-1-oxide, 8-hydroxy-
quinoline sulfate and metal salts thereof; 2,3-
dihydro-5-carboxanilido-6-methyl-1,4-oxathiin-
4,4 dioxide-2~3-dihydro-5-carboxanili-do-6-
methyl-1,4-oxathiin,~-(phenyl)-~-(2,4-dichloro-
phenyl)-5-pyrimidinyl-methanol (triarimol),
cis-N-[(1,1,2,2-tetrachloroethyl) thio]-4-
cyclohexene-1,2-dicarboxyimide, 3-[2-(3,5-
dimethyl-2-oxycyclohexyl-2-hydroxy]-glutarimide
20 -
52~
(cycloheximide), dehydroacetic acid, N-(l,l,-
2,2-tetrachloroethylthio)-3a,4,7,7a-tetra-
hydrophthalimide (captafol), 5-butyl-2-ethyl-
amino-4-hydroxy-6-methylpyrimidine(ethirimol),
acetate o~ 4-cyclododecyl-2,6-dimethylmorpholine
(dodemorph), and 6-methyl-2-oxo-1,3-dithiolo-
[4,5-b]quinoxaline (quinomethionate).
(d) miscellaneous halogenated fungicides such as
tetrachloro-p-benzoquinone (chloranil), 2,3-
dichloro-1,4-naphthoqui.none (dichlone), 2,3-
dichloro-2,5-dimethoxybenzene (chloroneb),
3,5,6-trichloro-o-anisic acid (tricamba),
2,4,5,6-tetrachloroisophthalo nitrile (TCPN),
2,6-dichloro-4-nitroaniline (dichloran), 2-
chloro-l-nitropropane, polychloronitroben.zenes
such as: pentachloronitrobenzene (PCNB) and
te~rafluorodichloroacetone;
(e) fungicidal antibiotics such as:
griseofulvin, kasugamycin and streptomycin;
(f) copper~based ~ungicides such as:
cuprous oxide, basic cupric chloride, basic
copper carbonate, copper naphthenate and
Bordeaux mixture; and
(g) miscellaneous fungicides such as:
diphenyl, dodecylguanidine acetate (dodine),
phenylmercuric acetate, N-ethylmercuri-1,2,3,6-
tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexa-
chlorophthalimide, phenylmercuric monoethanol
ammonium lactate, p-dimethylaminobenzenediazo
- 21 -
`
sodium sulfonate, methyl isothiocyanate~ l-
thiocyano-2,4-dinitrobenzene, l-phenylthio-
semicarbazide, nickel-containing compounds,
calcium cyanamide, lime sulfur, sulfur, and
1~2-bis(3-methoxycarbonyl-2-thioureido) benzene
(thiophenatemethyl).
The compounds of this invention can be advantageously
employed in various ways. Since these compounds possess
broad spectrum fungicidal activity, they can be employed
in the storage of cereal grain. These complexes can also
be employed as fun.~icides in turf, fruit orchards,
vegetables and golf course applications. Other applications
o~ the compounds of this invention will suggest themselves
to those skilled in the art o~ agriculture and horticulture.
The following examples illustrate the compounds o~
this invention and the methods by which they may be prepared.
However, the examples are illustrative only and it will
be apparent to those having ordinary skill in the art that
all of the products embraced by Formula I, supra, may also
be prepared in an analogous manner by substituting the
appropriate starting materials for those set forth in
the examples.
- 2~ -
...... ~`
76-78l~
~10~52~
EXAMPLE 1 - 3-Imi:~ophenylmethyl-4-(3-carbomethoxy-S-
meth~lisothi?ureido)benzophenone_
Sl;e~ A - ~-Iminophen~lmeth~1-4-aminobenzophenone
~o a solution of 3,~-diaminobenzophenone
(4.2~ g.; 0.02 mole) in methanol (50 ml.) cooled to O~C. is
added benzaldehyde (2.12 g.; 0.02 mole). ~he solution is
stirred aL 0C. for one hour. The prscipitate is collected
by filtration and dried to yield 3.0 g. of 3-iminophenyl-
methyl-4-aminobenzophenone, m.p. 112-116C.
Elemental analysis for c20T~16N20
Calc.: C, 79.97; H, 5.37; N, 9.33
Found: C, 80.11; H, 5.57; N, 9.28
Step B - 3-Iminophenylmethyl-4-(3-carbomethoxy-
thioureido~benzophenone
~o a solution of 3-iminophenylmethyl-
4-aminobenzophenone (0.5 g.; 0.00166 mole) in diethylether
(100 ml.) is added carbomethoxy isothiocyanate (0.19 g.;
0.00166 mole~. ~he solution is stirred at room temper~ture
for three hours. lhe precipitate is collected by filtration
and dried to yield 0.35 g. of 3-iminophenylmethyl-4-(3-
carbomethoxythioureido)benzophenone, m.p. 194-195~C. (dec.).
Elementa' analysis for C23~19N303S
Calc.: C, 66.17; H, 4.59; N, 10.07
Found: C, 65.81; H, 4.53; N, 9.80
Ste~ C - 3-Iminophenylmethyl-~-(3-carbomethogy-
S-methYlisothioureido)benzo~henone _
lo a solution of 3-iminophenylmethyl-
4-(3-carbomethoxythioureido)benzophenone (1.1 g.; 0.0026
mole) in dim~thylformamide (10.0 ml~) is added water
(3.0 ml.). Additional dimethylformamide (25.0 ml.) is
76-78
SZ~
added to dissolve some precipitate and th~3n sodium hydroxide
{50% aqueous; 0.21 g.; 0.0026 mole) is added. ~he resulting
solution is stirred at room temperature for 1-l/2 hours and
then methyl iodide (o.38 g.; 0.0026 mole) is added. ~he
solution is stirred for one hour at room temperature and
then poured into water (250 ml.). ~he precipitate is
collected by filtration and dried to afford 0.95 g. of
3-iminophenylmethyl-~-(3-carbomethoxy-S-methylisothioureido)
benzophenone, m.p. 140-1~2C. (dec.).
Elemental analysis for C24X21N303S
Calc.: C, 66.80; H, ~.91; N, 9.7
Found: C, 65068; H, 4.86; N, 10.4~
EXAMPLE 2 - 3-Iminophenylmethyl-~-(3-carbomethoxy-S-methyl-
isothioureido)benzoPhenone
To a suspension of 3-iminophenylmethyl-~-(3-
carbomethoxythioureido)benzophenone (2.09 g.; 0.005 mole)
in a mixture of acetone (20 ml.) and water (3.0 ml.) is
added aqueous sodium hydroxide solution (50~; 0.4 g.). ~he
mixture is stirred for one hour at room temperature. To the
solution is added methyl iodide (0.71 g.; 0.005 mole). Within
two minutes a thick suspension forms. ~dditional acetone (20
ml.3 and water (3.0 ml.~ is added and stirrin~ is continued
for 18 hours. ~he precipitate is collected by filtration and
dried to afford 2.05 g. of 3-iminophenylmethyl-~-(3-
carbomethoxy-S-methylisothioureido)benzophenone, m,p.
157-158C. (dec.).
Elemental analysis for C2~H21N303S
Calc.: C, 66.80; H, 4.91; N, 9.7~
Found: C, 66.31; H, ~.83; N, 9.95
Z4
~6-78~
5Zl
EXAMPLE ~ - 2-Imino(2,5-dichloro)phenylmethyl-4-(3-carbo-
methox~-S-meth~lisothioureido)benzophenone
~tep A - 2-Imino-(2,6-dicnloro)phenylmetnyl-4-
aminobenzophenone
~o an ice cooled solution of 3,4-
diaminobenzophenone (8.48 g.; 0.04 mole) in methanol
(100 ml.) is added a solution of 2,6-dichlorobenzaldehyde
(7.06 g.; 0.04 mole) in methanol (100 ml.). ~he solution
is stirred at 0C. for one hour and at room temperat1~ e
over the week-end. The precipitate formed is collected by
filtration and dried to afford 11.5 g. of 2-imino-~2,6-
dicnloro)phenylmethyl-4-aminobenzophenone, m.p. 141-144C.
Step B - 3-I~ino(2,6-dichloro)phenylmethyl-
4~ -carbomethox~thioureido)benzophenone
To a solution of 2-imino-~2,6-dichloro)-
phenylmethyl-4-aminobenzophenone (2.08 g.; 0.005 mole) in
diethyl e-ther (600 ml.) is added carbomethoxy isothiocyanate
(0.88 g.; 0.0075 mole). ~he solution is stirred at room
temperature for 18 hours. ~he precipitate which forms is
collected and dried to yield 1.8 g. of 3-imino(2,6-dichloro)
phenylmethyl-4-(3-carbomethoxythioureido)benzophenone, m.p.
197C. (dec.).
Elemental analysis for C23H17C12N303S
Calc.: C, 55.79; H, 3.52; N, 8.64
Found: C, 57.~9; H, 3.66; N, 8.84
Step C - 3-Iminophenylmethyl-4-(3-carbomethoxy-S-
metnYl-isothioure_ o)b_nz_Phenon~
~o a solution of 3-imino(2,6-dichloro)-
phenylmethyl-4-(3-carbometho~ythioureido)benzophenone (2.43
g.; 0.005 mole) in dimethylformamide (100 ml.) is added
water (5.0 ml~) and then sodillm hydroxide (50~ aqueous;
0.4 g.; 0~005 mole). ~he solution is stirred for 1-1/2 h~urs
~ 5 2 1
and then methyl iodide (0.71 g.; 0.005 mole) is added.
T'ne solution is stirred for one-hall hour. ~he pracipitate
which formS is collected b-y ~ilt~ation and dried to
afford 1.3 g. of 3-imin~phenylmethyl-4-(3-carbomethoxy-
S-methylisothioureido)benzophenone, m.p. 63-68C. (dec.).
Elemental analysis for C2 ~ 1gCl2N303S
Calc.: C, 57.60; H, 3.83; N, 8.40; S, 6.41
Found: C, 55.65; H, 3.8C N, 8.48; S, 5.84
EXAMPLE 4 - 3-Imino-(4-methylphenyl)methyl-4-(3-carbo-
ethoxY-S-meth~rlisothioureido)benzo~henone
SteP A - 3-Imino-(4-methylphenyl)methyl-4-
aminobenzo~henone
~o an ice cooled solution of 3,4-
diaminobenzophenone (6.36; 0.03 mole) in methanol
(75 ml.) is added ~-tolualdehyde (3.6 g.; 0.03 mole).
~he solution is stirred at 5C. for one hour and at room
temperat~re for 18 hours. A precipitate is collected by
filtration and dried to a~ford 4.5 g. of 3-imino-(4-
methyl)phenylmathyl-~-aminobenzophenone~ m.p~ 136-137C~
~ - 3-~mino-(~-methylp~snyl)methyl-4-
(~-carbomethox-~thioureido)benz?~henone
~o a solution of 3-imino-(4-methyl-
phe~yl)methyl-4-aminobenzophsnone (4.5 g.; 0.0145 mole)
in dimethoxyethane (75 ml.) and diethyl ether (25 ml.)
is added carbometho~ isothio-yanate (1.68 g.; 0.0145
mole). ~he solution is stirred at room temperaturefor 10
minutes ~t which time a precipitate begins to form.
Sr,irring is continued at room temperature for one ho~r
and the precipitate is collected by filt~ation and dried
to afford 3.9 g. of 3-imino-(4-methylphenyl)methyl-4-
(3-ca~bometho~Jthioureido)benzophenone, m.p. 201-202C.
(dec.).
26
':~'~1
~!
,~ .,
76-73~\
~ 5 2 1
Eiemental analysis for C24H21N3 3
Calc.: C, 66.80; ~, 4.91; N, 9.74
Found: C, 66.73; H, 4.79; N, 10.18
Ste~ C - 3-Imino-(4-meth~Jlphenyl)methyl-~-
(3-carbomethoxy-S-methylisothio-
ureido)~benzophenono __
To a solution of 3-imino-(~-methyl-
phenyl)methyl-~-(3-carbomethoxythioureido)benzophenone
(2.0 g.; 0.00463 mole) in dimethylformamide (100 ml.) and
water (5 ml.) is added sodium hydroxide (50~ a¢ueous; 0.37
g.). The solution is stirred at room temperature for one
hour at which time methyl iodide (0.66 g.; o. 00463 mole)
is added. The solution is stirred at room temperature for
20 minutes and then poured into water (1.0 1.). A
precipitate forms and is collected b~ filtration and dried
to afford 2.1 g. of 3-imino-(4-methylphenyl)m3thyl-4 (3-
carbomethoxy-S-mQthylisothioureido)banzophenone, m.p.
40-45Co (dec.).
Elemental æalysis for C25E23N303S
~ Calc.: C, 67.39; H~ 5.20; N, 9.43; S, 7.20
Found: C, 66.81; H, 5.22; N, 9.9~; S, 7.23
EXAMPLE ~ - 3-Imino-(4-chlorophenyl)~ethyl-4-(3-carbo-
meth,o,x~L-S-meth~lisothioureido)benzoPhenone
Step A - 3-Imino ~4-cnlorophenyl)methyl-4-
aminobenzophenone
To an ice cooled solution of 3,4-
dia~inobenzophenone (8.4 g.; 0.04 mole) in methanol (100
ml.) is added ~-chlorobenzaldehyde (5.6 g.; 0.0~ mole).
The solution is stirrad at 0-5C~ for one hour and at
room kemperatllre for 18 hours. The precipitate wnich
formis is collected and dried to afford 9.2 g. of 3-imino-
(4-chlorophenyl)~ethyl-4-aminobenzophenone, m.p. 123-125C.
76-78
ll~fL~SZl
~lemental analysis for 5 H ClN 0
Calc.: C, 71.74; H, 4.52; H, 8.37
Found: C, 7.87; H, 4.43; N, 8.60
Ste~ B - 3-Imino-(4-chlorophenyl)methyl-4-
(~-carbometho~gthioureido)benzop_en~ne
~o a solution of 3-imino-(4-chlo.o)-
phenylmethyl-4 aminobenzophenone (7.9 g.; 0.02 mole) in
diethyl ether (700 ml.) is added car~omethoxy isothio-
cyanate (2.34 g.; 0.02 mole). ~he solution is stirred at
room temperature for 18 hours. ~he precipitate which forms
is collected by filtrat-7On and dried to afford 6.6 g. of
3-imino (4-chloro~phenylm~thyl-~-(3 carbomethoxy-thioureido)-
benzophenone, ~.p. 212-216C. (dec.).
Elemental analysis for C23H18ClN303S
Calc.: C, 61.12; H, 4.01; N, 9.30
Found: C, 61.37; H, 4.06; N, 9.72
- 3,-I~ino-(4-chlorophenyl)methyl-4-
(3-carbomethoxy-S-methylisothio-
ureido)benzophenone
~o a solutlon of 3-imino-(4-chloro-
phenyl)methyl-4-(3-carbomethoxythioureido)benzophenone
(4.52 g; 0.01 mole) in dimethylformamide (200 ml~) and
water (5.0 ml.) is added aqu~ous sodium hydroxide (50%
aqueous; o.8 g.). ~he solution is stirred at room
temperature for one hour and then methyl iodide (1.42 g.;
0.01 mole) is added. ~he solution is stirred at room
temperature for 25 minutes and then poured into water
(700 ml.). The suspension which forms is then stirred
for 5 minutes and the precipitate is collected by
filtration and dried to afford 4.3 g. o~ 3-imino-(4-
chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothio-
ureido)benzophenone, m.p. 156-157C. (dec.).
- 28 -
76-78
~ 5 Z~
Elemental analysis ~or C24H20ClN303S
Calc.: C, 61.86j H, 4.33; N, 9.02
Found: C, 60.97; H, 4.21; N, 9.51
EXAMPLE 6 - 3-Iminophenylmethyl-4-(3-carbomet'noxy-S-
benzYlisothiourQdo)benzo~henone
To a solution of 3-iminophenylmethyl-4-(3-
carbomethoxy~hioureido)benzophenone ~2.~5 g.; 0.0054 mole)
in dimethylformamide (lO0 ml.) and water (10 ml.) there is
add~d aqueous sodium hydroxide solution (50~; 0.4~ g.).
~he solution is stirred at room temperatu~ for one hour
and then benzyl bromide (0.93 g.; 0.0054 mole~ is added.
~he solution is stir~ed at room temperature ~or 15 minutes
and is then poured into 500 ml. of water. ~he suspension
which forms is stirred at room temperatuxe for 5 minutes
and then collected by filtration and dried to afford
2.45 g. of 3-iminophenylmethyl-~-(3-carbomethoxy-S-
benzylisothioureido)benzophenone, m.p. 50-70C. ~dec.).
Elemental anal~s for C30H25N303S
Calc.: C, 70.98; H, 4.96; N, 8.28
Fo~md: C, 69.~4; H, 4.98; N, 8.90
EXAMPLE 7 - 3-Iminophenylmethyl-4-~3-carbomethoxy-S-
allvlisothio~reido)benzo~henone _ _
~o a suspension of 3-iminophen-~lmethyl-~-
(3-carbomethoxythioureido)benzophenone (2.09 g.; 0.005
mole~ in acetone (40 ml.) and water (6.0 ml.) is added
an aqueous sodium 'nydroxide solution (50~ aqueous; 0.4 g.).
~he suspension is stirred at room temperature for one hour
and then allyl bromide (0.6 g.; 0.005 mole) is added and
the solution is stirred at room temperature over the week-
enA. ~he precipitate which forms is collected by filtration
29
76-78~
l~rJ~5~1
and then dried to afford 1.3 g. of 3-iminophenylmethyl)-4-
(3-carbomethoxy-~-allylisothioureido)ben7Ophen3ne, m.p.
125-127C.
Elemental analysis for C26H23N303S
Calc.: C, 68.25; H, 5.07; N, 9.18
Found: C, 67.93; H, 4.93; N, 8.79
EXAMPLE 8 - 1-(3-Carbomethoxy-S-methylisothioureido)-2-
amino~henylmethyl-~-prop~lthiobenzene _ _
Ste~ A - 1-(3-Carbomethoxythioureido)-2-
nitro-5-propylthiobenzerle
~ a stirred mixture of 2-nitro-5-
propanyl~hioaniline ~1.2 g.; 0.10 mole) in acetonitrile
(50 ml.) isadded portionwise carbometh~xy isothiocyanate
(11.7 g.; 0.10 mole). ~he reaction mixture is maintained
av room temperature and is filtered to remove a small amount
of dark colored insoluble material. The clear filtrate
was permitted to stand at room temperature for two hours
an~ the precipitate which forms is collected by filtration,
washed with cold acetonitrile and dried to yield 1-(3-
carbom~thoxythioureido~-2-nitro-5-propylthiobenzene (17.9
g.), m~p. 122~-125C.
Ste~ B - 1~(3-Carbomethoxythioureido)-2-
amino-~-pro~ylthiobenzene
A mixture o~ 1-(3-carbomethoxythio-
ureido)-2-nitro-5-propylthiobenzene (~ g.; 0.013~ mole),
stannous chloride ~15.2 g.; 0.067 mole), concentrated hydro-
chloric acid (25 ml.), methanol (50 ml.) and aceti^ acid
(50 ml.) is stirred and refluxed for one half hour. ~he
reaction mixture is poured into ice water and basified
with 50~ aqueous sodium hydroxide solution. This solution
is extracted with dichloro~ethane and the dichloromethane
removed to afford 3.8 g. of l-(3 carbomethoxythioureido)-2-
amino-5-propylthiobenzene.
3o
76-78
~ 5 Z~
Step C - 1-(3-Carb~methoxythioureido)-2-
iminophenylmethyl-5-prop~lthio-
benzene
~o an ice-cooled solution of 1-(3-
carbomethoxythioureido)-2 amino-5-propylthiobenzene
(1.0 g.; 0.0033~ mole) in ri'ethanol (100 ml.) is added
benzaldehyde (0.35 g.; 0.00334 mole). The solution is
stirred at 5C. for an hour and the precipitate which
forms is collected by filtration and dried to afford 0.6 g.
of l-(3-carbomethoxythioureido)-2-imin3phenylmethyl-5-pro-
pylthiobenzene, m.p. 109-110C.
Elemental analysis for C19H21N302S2
Calc.: C, 58.89; H, 5.~6; N, 10.8`~
Found: C, 58.85; H, 5.46; N, 11.02
Step D - 1-(3-Carbo~ethoxy-S-methylisothio-
ureido)-2-iminop~enylmethyl-5-propyl-
thiobenzene_
~o a solution of 1-(3-carbomethoxythio-
ureido)-2-iminophenylmethyl-5-propyltAiobenzene (0.5 g~;
0.00129 mole) in acetone (20 ml.) and water (3.0 ml.) is
added an aqueous sodium hydroxide solution (50~; 0.103 g.).
The solution is stirred at room temperat~lre for 1-1/2 hours
and then msthyl iodide (0.183 g.; 0.00129 mole) is added.
lhe reaction mixture is sl.irred at room temperature for one
hourand then poured in water (100 ml.). ~he suspension
formed is stirred at room temperature for 1-1/2 hours an~
then the precipitate collected by filtration an~ dried to
afford 0.35 g. of 1-(3 carbomethoxy-S-methylisothioureido)-
2-iminophenylmethyl-5-propylthiobenzene, m.p. 80-83C.
33 (dec.).
Elem~ntal analysis for C20iI23N303S2
Calc~: C~ 59u82; X, 5.77; N, 10.~6; S, 15.97
Found: C, 59.73; H, 5.88; N, 10.3~; S, 15.89
76-7
SZl
EXAMPLE 9 - 1-(3-Carbomethoxy-~-methylisothioureido)-2-
iminophenylmethyl-4-benzen~r7sulfonylbenzene
Ste~ A - 2-I~inophenylmethyl-4-benzenesulfonyl-
aniline
~o an ice-cooled solution of 2-ami~o-4-
benzenesulfonylaniline ~5.2 g.; 0.021 mole) in methanol (25
ml.) is added benzaldehy~e t2.23 g.; 0.021 mole). ~he solu-
tion is stirred at 0C. for 1-1/2 h~urs. A suspension forms
which is stirred at room temperature overnight and then the
precipitate collected by filtration is ~ashed with methanol
and then ether and then dried to afford 6.0 g. of 2-
iminophenylmethyl-4-benzenesulfonylaniline, mOp~ 159-160C.
Elemental analysis for CL9Hl6N202s
Calc.: C, 67.83; H, 4.79; N, 3.33
Found: C, 67.54; H, 4.90; N, 8.62
~'ep B ~ 3-Carbomethoxythioureido)-2-imino-
~henylmeth~1-4-benæenesulfon.ylb~nzene
To a solution of 2-iminophenylmethyl-4-
benzenesulfonylaniline (4.5 g.; 0.0134 mole) in acetone
(250 ml.) is added carbomethoxy isothiocyan~te (1.57 g.;
0.0134 mole)~ ~he sollltion is stirred at room temperature
for two hours a~d the precipitate which forms is collected
by filtration, washed with et'ner and dried to afford 2.15
g. of 1-(3-carbomethoxythioureido)-2-iminophenylmethyl-4-
benzenesulfonylbenzene, m.p. 207-208C. (decO).
Elemental analysis for C22X19N304S2
Calc.: C, 58.26; H, 4.22; N, 9.27
Found: C, 58032; H, 4.14; N, 9.40
76-78
}S21
Step C - 1-(3-Carbomethoxy-S-meth~lisothioureido)-
2-iminophen~lmethyl-1+-benzenesulfonyl-
benzene
~o a suspension of 1-(3-carbo~ethoxy-
thioureido)-2-iminophenylmethyl-1+-benzenesulfonylbenzene
(1.0 g.; 0.0022 mole) in acetone (10 ml.) and water (1.0 ml.)
there is added an aqueous sodium h-Jdroxide solution (50~;
0.18 g.). This mixture is stirred at room temperature for
2 hours and a fine suspension which forms is removed by
filtration. ~o the filtrate is added methyl iodi~e (0.313
g.; 0.0022 mole). The solution is stirred at room temperature
~or 8 days. The reaction mixture is filtered and to the
filtrate is added water (300 ml.) and the resultin~ mixture
is stirred at room temperature for 3 h~urs. ~he precipitate
which forms is collected by filtration and dried to afford
0.3 g. of l-(3-carbomethoxy-S-m3t'nylisothioureido)-2-imino-
phenylmethyl-4-benzen~sulfonylbenzene.
Elemental analysis for C23H21N30l+S2
Calc.: C, 59.o8; H, 4.53; N, 8~99
Found: C, 58.67; H, 4.39; N, 8.79
EX~MPLE 10 - 3-Iminophen-~lmet'nyl-4-(3-carbomethox~-S-butyl-
isothioureido)benzophenone
~o a suspension of 3-iminophenylmethyl-l+-
(3-carbom~thoxythioureido)benzophenone (3.12 g.; 0.0075 mole)
in acetone (60 ml.) an1 water (10 ml.) there is added an
aqueous solution of sodium hydroxide (50%; 0.6 g.). ~he
mixture is stirred at roo~ temperature for 1-1/~+ hours and
to the solution form there is added n-butyl iodide (1.38 g.;
0.0075 mole). ~ne solution is stirred at room temperature
3 for 2 hours and the suspension which forms is collected by
filtration, washed with ether and dried to afford 1.9 g~
76-78l-~
~ 2 ~
of 3-iminophenylmethyl-4-(3-carbomethoxy-S-n-butylisothio-
ureido)benzophenone, m.p. 105-107C. (dec.).
Elemental analysis for C27X27N303S
Calc.: C, 68.47; H, 5.75; N, 8~87
Found: C, 67.56; H, 5.77; N, 8~52
EXAMPLE 11 - 3-Iminophenylmethyl-~-[3-carbomethoxy-S-(2,6-
dichlorophen"vl)isothiol~reido3benzophenon~
~o a suspension of 3-iminophenylmethyl-4-
(3-carbometho~Jthioureido)benzophenone (3.12 g.; 0~0075
mole) in acetone (60 ml.) a;~d water (10 ml.) is added an
aqueous solution of sodium hydroxide (50~; o.6 g.). ~he
mixture is stirred at room temperature for 2 hours and
then ~-bromo-2,6-dichlorotoluene (1.3 g.; 0.0075 mole) is
added. ~his solution is stirred at room temperaturefor
one half hour. ~he precipitate which forms is collected
by filtration, washed with ether and dried to afford 2.5
g. of 3-iminophenJlmethyl-4-[3-carbomethoxy-S-(2,6-di-
chlorophen~rl)isothioureido]benzophenone, m~p. 148-150C.
(dec.).
Elementa' analysis for C3~H23C12N
Calc.: C, 62.50; H, 4.02; N, 7.29
Found: C, 61.64; H, 3.95; N, 7.21
EXAMPLE 12 - 3-(Imino-(4-nitrophenyl)methyl-4-(3-carbo-
meth?x-~-S~methvlisothioureido)benzo~henone
S'.e~ A - 3-Imino-(4-nitrophenyl)methyl-4-
aminobenzopheno,ne_
~o a solution of 3,4-diaminobenzo-
phenone {8~48 g.; 0.04 mole) in methanol (100 ml.) is
added P-nitrobenzaldehyde (6.o4 g.; 0.04 mole). ~he re-
action mixture is stirred for 5 days and the precipitate
is collected by filtration and dried to afford 12.45 g.
of 3-imino-(4-nitrophenyl)methyl 4-a~inobenzophenone,
m.p. 161-163C. (dec.)~
~ 34 ~
76-78l~\
~ 5 21
Ste~ B - 3-Imino-(4-nitro~henylmeth-yl)-~-(3-
carbomethox~thioireido)benzoPhenone
To a solution of 3-imino-~4-nitro-
phenylmethyl-4 aminobenzophenone (6.9 g.; 0.02 mole) in
acetone (225 ml.) there is added carbomethoxy isothio-
cyanate (2.3~ g.; 0.02 mole). ~he solution is stirred at
room temperature for 18 hours. ~he precipitate which
forms is collected by filtration and then dried to
afford 7.35 g. of 3-imino-(4 nitrophenylmethyl)-~-(3-
carbomethoxythio~lreido~benzophenone, m.p. 229-230C.
(dec.).
Ste~ C - 3-Imino-(~-nitrophenyl)methyl-4-
(3-carbomethoxy S-methylisothio-
ureido)benzo-~henone
To a suspension of 3 imino-(~-nitro-
phen~Jlmethyl)-4 (3 carbomethoxythioureido)benzophenone
(4.62 g.; 0.01 mo'e) in acetone (160 m'.) and water (24
ml.)there is added an aqueous solution of sodium hydroxide
(50~; o.8 g.). ~he solution is stirred at room temperature
for one hour at which tlme methyl iodide (1.42 g.; 0.01
mole) is added. ~he Sllspension forms and the reaction
mixture is stirred for 30 minutes. lhe precipitate is
collected by filtration, washed with ether and dried to
afford 2.55 g. of 3-imino-(4-nitrophen-~l)methyl-4-(3-
carbomethoxy-S-methylisothioureido)benzophenone, m.p.
180-182C. (dec.).
Elemental analysis for C24~2oN405S
Calc.: C, 60.49; H, 4.23; N, 11.76
Found: C, 60.90; H, L.33; N, 11.87
~ 5 21
EXAMPLE l~ - 3-Imino-(2~ap~hylmethy~-4 (3-carbometho~y-
Step A - 3~Imino-(2-naphthy ~ thyl )-4-amino-
benzoPhenone
~o an ice cooled solution of 3,4-
diaminobenzop'nenone ~10.6 g.; 0.05 mole) in-methanol
(120 ml.) is added 2-sphthy ~ thyl (7.8 g.; 0.05 mole).
The solution is stirred at 5C. for 2 hours at room
temperature overnight. Sulfuric acid (5 drops) is added
10 and the solution st~ red an additional 5 days at room tem-
perat~re. ~he ~re~ipitate is collected by fil~ration and
dried to afford 5.25 g. of 3-imino-(4-nitrophenyl)methyl-~-
aminoben20phenone, m.p. 141-143C. (dec.).
Elemental analysis for C24H18N20
Calc.: C, 82.26; H, 5.18; N, 8.00
Found: C, 81.53; ~, 4.98; N, 7.19
SteP B - 3-Imino-(2-~a~hthylmethy~ (3-
ca~bomethox~It -oureido)benzo~henone
~o a solution of 3-imino-(2-naphthyl)
20 4-(aminobenzophenone) (4.0 g.; 0. OllL~ mole) in acetone (50
ml.) is add~d carbomethox~ isothiocyanate (1.34 g.; 0.0114
mole). A suspension forms within 5 minutes and stirring
is continued at room temperature for 18 hours. ~hs pre-
cipitate is collected by filtration, washed successively
25 with acetone and ether and then dried to af~ord 3.1 g. of
3-imino-(2-naPhthY ~ ~Y~ 3-carbomethoxythioureido~-
benzophenone, m.p. 207-209C. (dec.~.
Elemental analysis for C27H2~M303S
Calc.: C, 69.36; H, 4.53; N, 8.99
Found: C, 69~37; H, 4.58; N, 8.83
; 36
5~ '
Ste~ C - 3-Imino-~2-r~phthyllrethy~ (3-
carbomel;ho~y-S-msthylisothioureido)-
ben~.o~henone ,.. .
'rO a suspension of 3-imino-(2-naphthyl-
methyl)-~-(3-carbomethoxythioureido)benzophenone (2.5 g.; r
0.0535 mole) in acetone (25 ml.) and water ~3 ml.) there
is added an aqueous sodium hydroxide solution (50~; 0.43 g.).
The mixture is stirred at room temperature ~or 18 hours and
then filtered. To the filtrate is added methyl iodide
(0.76 g~; 0.00535 mole). The precipitate for~rs within 5
minutes. ~he suspension is stirred at room temperature
for 30 min~ltes arld the precipitate is collected by filtration,
washed with ether and dried to af~ord o.8 g. of 3-imino-
(2- naphthyl methyl)-4-(3-carbomet~ox-y-s-methylisothioureido)
benzopheilone, m.p. 147-149.5C. (dec.).
EleD;ental analysis for C28~I23N303S
Calc.: ~, 69.83; ~I, 4.81; N, 8.73
Found: C, 69.28; H, 4.82; N, 8.50
EXAMPLE lL~ - 3-Imino-(4~methoxyphenylmethyl) 4-(3 carbo-
methoxy-S-methylisothioureido~benzophenone
Ste~ A - 3-Imino-~4-methoxyphenylmethyl~
aminobenzo~hsnone
~o an ice-cooled solution OI 3,4-
diaminobenzophenone (10.6 g.; 0.05 mole) in methanol (120 ml.)
is added ~-anisaldehyde (6.8 g.; 0.05 mole). ~he solution is
stirred at 5C~ for 2 hours and at room tempe~ature for 18
hours. Sulfuric acid (5 drops) is added to the solution and
it is stirred an additional 9 days at room temperaturQ.
~he precipitate is collected by filtration, washed with ether
and then dried to afford 4.2 g. o~ 3-amino-(4~ethoxyphenyl-
methyl)-4-aminobenzophenone, m.p. 129-131~. ~dec.).
h~-~
, ~ ,
76-78l~
~lU~;2~
Step B - 3-Imino-(4-methoxyphen~lmethyl)-~-
~-carbomethoxvthioureido)benzoPheno~e
To a soluti~n ~f 3-imino-(~-metho~J-
phenylmetnyl)-~-aminobenzophenone (4.29 g.; 0.0127 mole)
in aceto~e (75 ml.) is added carbomethoxy isothiocyanate
(1.49 g.; 0.027 mole). ~he solution is stirred a', room
temperature for 18 hours (a precipitate forms within 3
minutes). ~ke precipitate is collected by filtration,
washed with ether an~ then dried to afford 3.3 g. of
3-imino-(~-methoxyphenylmeth-~1)-4-(3-carbomethoxythio-
ureido)benzophenone, m.p. 182-18~C. (dec.).
Step C - 3-Imino-(4-met~yphenylmethyl) 4-(3-
carbomethoxy-S-methylisothioureido)-
benzo~hen,~ne __ _
To a suspension of 3-imino-(4-methoxy-
phenylmethyl)-~-(3-carbomethoxythioureido)benzophenone (2.5
g.; 0.0056 mole) in acetone (20 ml.) and water (~ ml.) there
is added an aqueous solution of sodium ~ydroxide (50%; 0.45
g.). Ths reaction ~ixture is stirred at room temperature
for two hours. A solid which forms is removed by filtra-
tion and to the clear filtrate is added methyl iodide
(0.79 g.; 0.0056 mole). A precipitate forms within 5
minutes~ ~he suspension is stirred a' room temperature
for 30 minutes and the precipitate is collected by filtra-
tion, washed with ether and dried to afford 1.1 g~ of
3-imino-(4-m-thoxyphenylmethyl)-~(3-carbomethoxy-S-
methylisothioureido)benzophenone, m.p. 136-13~3C. (dec.).
Elemental analysis for C25'H23N30,~S
Calc.: C, 65.06; H, 5.02; N, 9.10
Found: C~ 6~.87. H, 5.0~; N, 8.87
- 38-
76-78l~
~ 21 ,,
EXAMPLE 15 - 3-Imino-(2-nitrophenylmethyl)-4-(3-carbo-
meth~x~--S-methylisothioureido~benzo henone
Ste~ A - 3-Imino-(2-nitrophenylmethyl)-4-
aminobenzophenone
~o an ice-cooled solution of 3,4
diaminobenzophenone (8.48 g.; 0.04 mole) in methanol
(100 m .) there is added o-nitrobenzaldehyde (6.04 g.;
0.04 mole). The mixture is stirred a'~ 5C~ for one hour
and at room temperature for 18 hours. Sulfuric acid (3
drops) is added to the solution and then within one hour
a suspension forms. ~he suspension is stirred at room
temperature for 18 hours and a precipitate collected by
filtration, washed with et'ner and dried to afford 10.85 g.
of 3-imino-(2 nitrophenylmethyl)-4 aminobenzophenone,
m.p. 140-142C. ~dec.). This material is used in the
next step without further purification.
Step B - 3-Imi;o-(2-nitroph3nylmethyl)-4-(3-
carbomethox~thioureido)benzo~,henone
~o a solution of 3 imino-(2-nitro-
phenù71meth~1)-4-aminobenzophenone (10.0 g.; 0.029 mole)
in acetone (100 ml.) is added carbomethoxy isothiocyanats
(3.4 g,; 0.029 ~ole). ~he solution is stirred at room
temperature for 3 hours and the precipitate coll~cted by
filtration and dried to afford 7.3 g. of 3-imino-(2-nitro-
phenylmethyl)-4-(3-carbomethoxythioureido)benzophenone,
m.p. 215-217C. (dec.).
Element,al analysis for C23H18N~05S
Calc.: C, 59.73; H, 3.92; N, 12.12
Found: C, 59.65; H, 3.98; N, 12.28
- 39 -
76-7~i~
S21
Step C - 3-Imino-t2-nitrophenylmethyl)-4-(3-
carbomethoxy-S-methylisothioureido)-
benzophenone
~o a suspension of 3-imino-(2-nitro-
phenylmethyl)-4-(3-carbomethoxythioureido)benzophen~ne
(4.62 g.; 0.01 mole) in acetone ~160 ml.) and water (24 ml.)
is added an aqueous solution of sodium hydroxide (50%;
0.8 g.). ~he mixture is stirred at room temperature for
one hour anl a fine precipitate which forms is removed
by filtration. lo the filtrate is added methyl iodide
(1.42 g.; 0.01 mole~ and the solution stirred at room
temperature for 45 minutss. Ihe precipitate which forms
is collected by filtration and dried to afford 2.65 g.
of 3-imino-(2-nitrophenylmethyl~-4-(3-carbometh~xy-S-
methylisothioureido)benzophenone, m.p. 167-168.5C. (dec.).
Elemental analysis for C24H20N405S
Calc.: C, 60.49; ~, 4.23; N, 11.76
Found: C, 60.55; X, 4.26; N, 11.65
EXAMPLE 16 - 3-Imino-(3,4-dichlorophenylmethyl)-4-(3-
carbomethox~-S-meth~liso'.hioureido)benzophenone
Ste~ A - 3-Imino-(3,4-dichlorophenylmethyl)-~-
aminobenzoPhenorle
To a solution of 3,4-diaminobonzo-
phenone (6.15 g.; 0.029 mole) in methanol (103 ml.~,
cooled to 5C., is added 3,4-dichlorobenzaldehyde (5.08 g.;
0.029 mole). ~he mixture is stirred at 5C. for one hour
and at room temperalure for 18 hours. ~he precipitate
which forms is collected by filtration and dried to afford
7.96 g. of 3-imino-(3,4-dichlorophenylmethyl)-4-amino-
benzophen~ne, m.p. 147-148C.
76 -78,~
S21
Elemental analysis for C20EI14C12N20
Calc.: C, 65.05; H, 3.82; N, 7.59
Found: C, 64.60; H, 3.79; N1 7.49
Step_B - 3-Imino-(3,4-dichlorophenylmeth~J1)-~-
(~-carbomethox~thioureido)benzophenone
~o a solution o~ 3-imino-~3,~-
dichlorophenylmethyl)-~-a~inobenzophenone (7.0 g.; 0.019
mole) in acetone t200 ml.) there is added carbomethoxy
isothiocyanate (2.22 g.; 0.019 mole). A precipitate forms
within five minutes. The mixture is stirred at room
temperature for 1-1/2 hours and the precipitate which forms
is collected by filtration, washed with acetone and then
ether and then dried to afford 6.9 g. of 3-imino-~3,4-
dichlorophenylmethyl)-~-(3-carbomethoxythioureido)benzo-
phenone, m.p. 214-126~C. (dec.).
Elemental analysis for C23X17C12r~303S
Calc.: C, 56.79; H, 3052; N, 8.6
Found: C~ 56.76; H, 3.53; N, 8.43
Ste~ C - 3-Im no-(3,~-dichlorophenylmethyl~-4-
(3-carbomethoxy-S-methylisothioureido)-
benzoPhenone
To a solution of 3-imino-(3,4-dichloro-
phenylmethyl~-~-(3-carbomethoxythioureido)benzophenone
(3.0 g.; 0.0062 mole) in dimethylformamide ~225 ml.) and
water (10 ml.) there is added an aqueous sodium hydroxide
solution (50%; 0.49 g.). The solution is stirred at room
temperature ~or one hour and then methyl iodide (0.88 g.;
0.0062 mole) is added. ~he solution is stirred at room
'emperature for 20 minut~s and then poured into water
(1.0 1.). The susp~nsion is filtsred to collect the
precipitate and then dried to afford 2.55 g. of 3-imino-
(3,4-dichlorophenylmethyl)-~-~3-carbomethoxy-S-methyliso-
thioureido)benzophenone, ~.p. 168-174C. (dec.).
- 41
76-78~.
521
Elemental analysis for C2~H19C12N303S
Calc.: C, 57.60; H, 3~83; N, 8.40
Found: C, 57.22; H, 3.79; N, 8.24
E~ PLE 17 - 3-Imino-(2-chlorophenylmethyl)-4-(3-carbo-
methoxy-S-methylisothioureido)benzophenone
Step A - 3-Imino-(2-chlo,ophenylmethyl)-4-
aminobenzo~henone
To an ice-cooled solution of 3,4-
diaminobenzophenone (16.96 g.; 0.08 mole) in methanol
(200 ml.) is added o-chlorobenzaldehyde (11.2 g.; 0. o8
mole). The solution is stirred at room temperature for
30 minutes and the precipitate which separates is
collected by filtration and dried to afford 20.5 g. of
3-imino-(2-chlorophenylmethyl~-4-aminobenzophenone, m.p.
112C. ~dec.).
Step B - 3-Imino-(2-chlorophenylmethyl)-~-
(~-carbomethoxythioureido~benzophenone
To a solution of 3-i~ino-(2-chloro-
phenylmethyl)-4-aminobenzophenone (11.85 g., 0.03 mole) in
acetone (100 ml.) is added carbomethoxy isothiocyanate
(3.51 g.; 0.03 mole). It is necessary to add another
portion of acetone (100 ml.) to the thick suspension which
forms. The reaction mixture is stirred for an additional
30 minutes and the precipitate collected by filtration and
dried to afford 9O0 g. of 3-imino-~2-chlorophenylmethyl~-4-
~3-carbomethoxythioureido)benzophenone, m.p. 204-205C.
(dec.).
Elemental analysis for C23H18ClN303S
Calc.: C, 61.12; H, ~.01; N, 9.30
Found: C, 60.93; H, 4.00j N, 9.19
42
76-78 It
S 21
Ste~ C - 3-Imino-(2-chlorophenylmethyl)-4-
(3-carbomethoxy-S-methylisothio-
ureido~benzop_enone
~o asuspension of 3-imino-(2 chloro-
phenylmethyl)-4-(3-carbomethoxythioureido~benzop~enone
~3.0 g.; 0.0066 mole) in acetone (50 ml.) and water
(10 ml.~ is added an aqueous solution of sodium hydroxide
(50~; 0.53 g.~. ~he mixture is stirr~d at room temperature
for one hour and then methyl iodide (0.94 g.; 0.0066 ~ole)
is added. ~he solution is stirred at room temperature
o~er the week-end and the precipitate -~Thich forms is
collected by filtration and dried to afford 0.9 g. of 3-
imino-(2-chlorophenylmethyl)-4-(3~carbomethoxy-S-methyl-
isothioureido)benzop'nenone, rn.p. 140-142C. (dec.).
Elemental analysis for ~,24H20ClN303S
Calc.: C, 61.86; H, 4.33; N, 9.02
Found: C, 61.76; H, 4~40; N, 8.80
EXL~IPLE 18 - 3-I~nino-(4-dimethylaminop~enylmethyl)-4-(3-
carbomethoxs-S-meth~Ilisothioureido)benzo~henone
Ste~ A - 3-Imino-(4-dimethylaminophenylmethyl)-
4-aminobenzophenone
~o an ice-cooled solution of 3,4-
diaminobenzophenone (8.48 g.; 0.04 mole) in methanol (100
ml.) is added p-N,N-dimethylaminobenzaldehyde (6.0 g.; 0.04
mole). ~he mixture is stirred at 5C. for on~ hour and at
room temperature for 18 hours. Sulfuric acid (3 drops) is
added to the reaction mixtu-^e and within one hour a thick
suspen;,ion forms. ~he reaction mixture is stirred at room
te~peralul~e for an additional 8 hours and the precipitate
3o is collected and dried to afford 10.2 g. of 3-imino-(4-
dimethylaminophenylmethyl)-4-aminobenzophenone, m.p.
171-173C. (dec.).
43
76-781~
S2~
El?mental analysis for C~2E21N30
Calc.: C, 7O.94; H, 6.16; N, 12.24
Found: C, 76.08; H, 6.17; N, 12.03
Step,B - 3-Imino-(4-dimethylaminophenylmethyl~-
4-(3-carbomethoxythioureido)benzo-
phenone
To a solution of 3-imino-(~-dimethyl-
aminophenylmethyl~-4-aminob~nzophenone (9.6 g.; 0.0262 mole)
in acetone (2 1.) there is added carbomethoxy isothiocyanate
(3.0 g.; 0.0262 mole). ~he solution is stirred at room
temperature for 10 days and the acetone removed under
vacuum. The residue is slurried in 100 ml. of acetone
and filtered and washed with ether and then dried to afford
8.o g. of 3-imino-(4-dimethylaminophenylmethyl)-4-(3-
carbomethoxythiollreido)benzophenone, m.p. 199C. (dec.).
Elemental analysis for C25H2~N403S
Calc.: C, 65.20; H, 5.25; N, 12.17
Found: C, 65.05; H, 5.25; N, 11.98
Step C, - 3-Imino-(4-dimethylaminophenylmethyl)-
4-(3-ca:^bomethoxy-S-methylisothio-
ureilo)benzo~henone
~o a suspension of 3-imino-(4-dimethyl-
aminophenylmethyl)-~-(3-carbomethoxythioureido)benzophenone
(3.0 g.; 0.0065 mole) in acetone (50 ml.) and water (10 ml.)
there is added an aqueous solution of sodium hydroxide
(50~; 0.52 g.). ~he mixture is stirred at room temperature
for one hour and then methyl iodide (0.93 g.) is added. ~he
solution is stirred at room temperature for one hollr (a
precipitate begins to form after 15 minutes). ~he pre-
cipitate which forms is collected by filtration and driedto afford 0.6 g. of 3-i~ino-(4-dimethylaminophen,rlmeth-vrl)-
4-(3-carbomethoxy-S-methylisothioureido)benzophenone,
m.p. 143-14~C. (dec.)~
- 44 -
76-7sr~
52
Elemental analysis for C22H21N30
Calc.: C, 76.94; H, 6.16; N, 12.24
Found: C, 76.08; H, 6.17; N, 12.03
EXAMPLE 19 - 1-Imino~ -chlorophenyl)methyl-2-(3-car~o-
methoxy-S-methylisothioureido)-4-propylthio-
benzene
Step A - l-Imino-(~-chlorophenyl)methyl-2-
(3-carbomethoxythioureido)-4-propyl-
thiobenzene
l~o an ice-cooled solution of 1-
amino-2-(3-carbomethoxythioureido~-4-propylthiobenzene
(3.0 g.~ in absolute methanel (100 ml.) there is added
finely divided ~-chlorobenzaldehyde (1.4 g.). ~he
yellow solution formed is stirred at 5C. for one hour
(precipitate forms after 10 minutes~. The precipitate
is collected by filtration. 'rhe yellow solid is dried to
afford 1.2 g. of 1-imino-(p-chlorophenyl)methyl-2-(3-
carbometho~ythioureido)-4-propylthiobenzene, m.p. 170-
172C. (dec.~.
Elemental anal~Jsis for C19H20ClN302S2
Calc.: C, 54.08; H, 4.78; N, 9.9~
Found: C, 54.0~; H, 4.80; N, 9.89
SteP B - l-Imino~ chlorophenyl)methyl-2-(3-
carbomethoxy-S-methylisothioureido)-
4-PropYlthiobenzene
~o a suspension of l-imino-(P-
chlorophenyl)methyl-2-(3-carbomethoxyisothioureido~-4-
propylthiobenzene (1.2 g.~ in acetone (30 ml.) and water
~10 ml.) is added sodium hydroxide (0.23 g.; 50~ aqueous ).
~he mixture is stirred at room temperature ~or one hour and
to the solution formed there is added methyl iodide (0.4 g.).
A precipitate forms immediately and the suspension is
~ 45 -
76-78 !
~S21
stirred at room temperature for 30 minutes. ~he p-ecipitate
is collected by filtration, washad with ether and dried to
afford 1.05 g. of 1-imi~o-(~-chlorophenyl)methyl-2-(3-
carbomethoxy-~-methylisothioureido)-4-p~opylthiobenzene,
~.p. 139-1~0C.
Elemental analysis for C20H22ClN302S2
Calc.: C, 55.09; X, 5.09; N, 9.64
Fownd: C, 54.28; H, 5.06; N, 9.29
EXAMPLE 20 - 1-Imino-(2-thienyl)methyl-2-(3-carbomethoxy-
~~ S-m~th~lisothioureido)-4-~ro~ylthiobenzene
Step A - l-Imino-(2-thienyl)methyl-2-(3-
carbomethoxythioureido)-4-
thiobenzene
To an ice-cooled solution of 1-
amino-2-(3-carbomethoxythioureido)-4-propylthiobenzen~
(3.0 g.) in methanol (75 ml.) there is added 2-thio-
phenecarboxaldehyde (1.12 g.). The solution immediately
cnanges to a yellow color and within 15 mi.~utes a
precipitate forms. The suspension is stirred at 5C.
for one hour and at roo~ temperature for 24 hours. The
solid is collected by filtration and dried l;o afford 1.05
g. of l-imino-(2-thienyl)met:~yl-2-(3-carbomethoxy-S-
meth~Jlisothioureido)-~-propylthiobenzene, m.p. 123-124C.
Elemental analysis for C17H19N302S3
Calc.: C, 51.88; H, 4.87; N, 10.68
Found: C, 51.52; H, 4.92; ~, 10.63
46
76-78
~ 5 2~
S-5e~ B - l-Imino-(2-thienyl)methyl-2-(3-
carbom~thoxy-~-methylisothioureido)-
lt-proT)~ll I;hiobenzene
~o a ~ixture of l-im~no-(2-thien71)-
methyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene
(1.0 g.) in acetone (20 ml.` an~ water (7 ml.), there is
added a 50~ aqueous sodium hydroxide solution (0.203 g.).
The mixture is stirred at room temperature for one h~ur.
A solution forms after 15 minutes and to it is added methyl
iodide to.36 g.~. The sollltion is stirred at room
temperature for two hours and the precipitate formed is
collected by filtration and dried to afford 0.55 g. of
l-imino-(2-thienyl~methyl-2-(3-carbomethoxy-S-methyliso-
thioureido)-4-propylthiobenzene, m.p. 95C. (dec.).
EXAMPLE 21 - 1-Imino-(~-cnlorophenyl)methyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4 phenyl-
thiobenzene
Step A - l-Imino-(P-cnlorophenyl)methyl-2-
(3-carbomethoxythioureido)-~-
~hen~lthiobenzene
To an ice-cooled solution ~f l-amine-
2-(3-carbomethoxythiourei~10)-4-phenylthiobenzene (3.33 g.)
in anhydrous methanol (300 ml.) is added finely powdered
~-chlorobenzaldehyde (1.~ g.). ~he sollltion is stirred at
5C. for one ho~lr (a precipitate b~gins to form after 15
minutes). ~he solid formed is collected by filtration
and dried to afford 2.6 g. of l-imino-(~-chlorophenyl)-
methyl-2-(3-carbomethoxythioureid~)-4-phenylthiobenzene,
m.p. 170-172C.
- l-Imino-(~-chlorophenyl)methyl-2-
(3-carbomethoxy-S-methylisothio-
ureido ? -4-~henYlthiobenzene
To a suspension of l-imino-( -
chlorophenyl)methyl-2-(3-carbomethoxythioureido)-~-
47
76-78~
S21
phenylthio~enzene (1.6 g.;.00351 mole) in aceton~ (30 ml.)
and water (10 ml.) is added sodium llydroxide ~50~ aqueous;
0.28 g.). ~he mixture is stirred at room temperature for
one hour and to the solution formed there is added methyl
iodide (0.5 g.). A precipitale ~orms within ~ive minutes
and the suspension is stirred at room temperature for 30
minutes. ~he precipitate is collectsd and dried toafford
1.02 g~ of 1-imino-(P-chlorophenyl)methyl-2-(3-carbomethoxy-
S-methylisothioureido)-L~-phenylthiobenzene, m.p. 135-136~.
Elemental analysis for C23E20ClN302S2
Calc.: C, 58.77; H, 4.29; N, 8.9~
Found: C, 57.90; H, ~.20; N, 8.77
EXAMPLE 22 - 3-Imino-(2 thienyl)methyl-~-(3-carbomethoxy-
S-meth~lisothioureido)benzo~heno~e
A mixture of 3-imino-(2-thienyl)methyl-~-
(3-carbomethoxythioureido)benzophenone (1.0 g.; 0.062~ mole)
in acetone (L2 ml.) and water (4 ml.) containing aqueous
sodium hydroxide (0.22 g.; 0.002~ mole; 50~) is stirred at
room temperature for one hour and methyl iodide (0.4 g.) is
added. A precipitate forms almos'. i~mediately, filtered
and the solid washed with water and drisd to afford 0.7 g.
of 3-imino-(2-thienyl)methyl-~-(3-carbomethoxy-S-methyliso-
thioureido)benzophenone, m.p. 168-170~. (dec.); 67% yield.
EXAMPLE 2~ Iminophen~lmethyl-2-(3-carbomethoxy-S-all~l-
isothioureido)-~-~ro2~1thiobenzene
~o a suspension of l-iminophenyl~ethyl-2-(3-
carbometh~xythiourei~o)-~-propylthiobenzene (1.0 g.~ in
acetone (30 ml.) and water (10 ml.) there is added aqueous
sodium hydroxide (0~21 g.). ~he mixture is stirred at room
temperature for one hour (a solution forms 20 minutes after
the addition of sodium hydroxide) and to it there is added
-48 ~
76-78~
S21
allyl bromide (0.36 g.). The solution is stirred at room
temperature for two hours and is then poured into water
(300 ~1.). ~he mixture is stirred at room temperature
for 24 hours and is vacuum filtered. The tacky yellow
solid is stirred in hexane (50 ml.) and is filtered to
yield 0.35 g. of 1-iminohexylmethyl-2-(3-carbomethoxy-~-
isothioureido)-~-propylthiobenzene, m.p. 70~-72C.
In a manner similar to that described in the
written examples, all of the 2-imino substituted thio-
L0 ureidobenzenes (I) of this invenlion may be prepared bybeginning with an appropriately substituted l,2-diamino-
benzene co~pound and following substantially the procedures
described herein. The following equation illustrates the
various reactions which maJ be employed and taken together
with Iable I, infra, depict the starting materials, inter-
mediates and final products ob=airled.
- 49-
7 ~-78,~
'52
~2
NH2
O / Va
S-C=NCORl / \ R2CHO
IV
1~ ~
X
~NH2 ~J-CTC[R2
NHCINFICO 2Rl N~12
Base \ R2cHo ~ S=C=N~OR
~3 or
RSO3R
or ~ X
RS04R ~ =C.~2
NHCNHCO 2R
II S
~) -Ba s e
3-R -Ha l
or
RS04R
X
RZC~IO ~_CHR2
irH=NC02R.' ~HC,-NC02R
SR . SR
IIa
~ ~n -
76 -78~ -
llOC}S21
TABLE I
E:x.R Rl R2 X
N3.-- O
24-C2H5 -CH3
25-C3H7 -C2H5 ~ Cl ~
26-C4H9 -n-C3H7 C~ "
275 11 -iso-C3E7 ~53
28C6H13 -n-C4H9 _~
29-C7E15 _iso-CL~E9 _~
30C8H17 -tert-C,.Hg ~ 3
31~ (C~2) 2C~I CH2 c~clo-c5H9 ~ 3 "
32 -(CH2)3CE=cH2 Cvcl-c6H~
33 -(CH2)4CH=C~2 -GH3 ~C2H5 "
34 - (CH2) 5CX=CH2 -CH3 _~C2X5
C2~5
3 5 - (CH2 ) 6CX=CX2 -CH3
ot~
110~521
~ABLE I (cont.)
Ex. R Rl R2 X
No. O
36 -CH2C--CH -CH3 ~ (5)-C
37 -(CH2)2c-cH -CH3 ~ "
O
38 ( 2 3 -CH3 ~ (5)-CCH3
o
39 -(C~2)4C-CH -CH3 ~ (5)-cc2H5
-(CH2)sc-cE -C~3 ~ (5)-CC3H7
41 (CH2)6C-CH -C:~3 ~ o ~5)-CC4H9
42 CX ~ -C~X_ ~ NO2 (5)-oCH3
43 -CH2CE2 ~ C2H5 ~ (4)-oc2x5
02N
44 -CF2 ~ -CX3 ~ (4)-OC3H7
02N
-CH2 ~ -C3H7 ~ ~ (4)-Oc4H9
46 -CH2CH2 ~ -CE3 ~ ~ N (4)-oc5~9
47 -CH2CH2CH2 ~ -tert ~4H9 ~ (5)-SCN
76-78~\
110~52~
TABLE I (cont.)
Ex. R Rl R2 X
~8 CH ~ Cl -tert-C~H9 ~ -OCH3 (5) -SO
~9 -C~2 ~ C~3 -C'~3 ~ OC~3 ~5~-So2
-CH2CH2 ~ OC~3 -CH3 ~ (4)-SO
51 -(CH2)3-0 ~ -CT~3 ~ (5~--S2
CX3CO
52 -(CX2)4-0 ~ 3 ~ ~ (4)-~CH3
53 (CH2)5 ~ c~clo-c5H9 ~ F (~ C3H7
(CH2)6 ~ c~c10-~5H9 ~ CH (5)-SOC3H7
-CX2 ~ -n-C3H7 ~ C~ (5)-so2cH3
56 ( 2)2{~ -a-C3H7 -n-C3~7 0
57 -CH2{) -CH3 -n-C4H9 (4)-NHCCH3
58 (CH2) 2~ -C2H5 -n-C5Hll ( 5) -NHC{~
59 -(CH2)3CN -CH3 ~ 5 11 (4)-NHC~
76-78 ~'
S~:l
~ABLE I (cont. )
No. R Rl R2 X
~ (CH2)4GN CH ~ Cl (4~ -NHc-oc2H5
61 ~ ( CH2 ) 5C~ -CH3 ~ ( 5~ -NHRC -O -CH/ 3
Il
62 - (C-d2 ) 6CN - CH3 ( 4 ) -NHC -OC4H9
63 -(CX2)30H " ~ ( ) ii~;9
64 - (CH2)40H `' Cl ( 4 ~_ S4
~ (CH2) 5~ ~ (5) _
(CH2 ) 8 (5) ~ ; 2 ~
67 -CH=CHCH24~ " " (5)-C4~-CL
68 -(CX2)30C~'13 1~ " (5)-C~30C-~
69 ( 2 3 2 5 " (5) -C~c~3
(C 2)L~ 3 -C~13 0
71 ~ (CH2)~0c3H7 -C3H7 " (5) -C~-CF3
7 2 ~ ( CX2 ) 3C -O CH3 C 2H5 ( 5 ) -C
-- 54 --
76-78A
S21
~ABLE I (cont.)
Ex.
No. R R R2 X
O O
73-(C~2)4C~C2~5 C2H5 ~ C. (5)-C ~
74-(C'~'I2)5cc2~5 " " (~-SO ~ CN
O ' O
75-(CH2~5C-OC3H7 -C3H7 ~ ~ 3
,0
76-(CH2)4- ~ ~ -C~3 " (~-S2 ~ CN
77-(CH2)3c- ~ ~ ( 4) S2 ~ -CCE3
78(CX2)~C-0 ~ " (4)-S ~ CN
2 5 ~
30-(CH2)6C-O ~ " ,t ( ~C~Hg-n
81 -C4Hg " ~ H
N ~ g
82 -C3H7 -C2H5 ~ (4) -C-
83 -C2H5 -C3H7 ~ "
84 -CH3 -C4Hg ~ ,N
85 -C4Hg -C3H7 N~ N
- 55 -
76-78A
110~21
Ex. 2
No. R Rl R X
86 -C3H7 -C2H5 ~ (5) -C-
N
87 -C2H5 -CH3 ~ N H
88 -CH3 -CH3 ~ H
89 -C4Hg -C2H5 ~ H
~CH3
-C4Hg n-C4Hg ~ H
91 -C3H7 tert-C4Hg ~ 1~ (5)-C3H7
92 -CH3 tert-C4Hg ~ ~ (4)-C4Hg
93 -C4Hg tert-C4Hg ~ (4)-C2Hs
- 5~ -
76-78~
110~
EXAMPLE 94 - 1-Imino(2-furylmethyl)-2-(3-carbomethoxy-S-
benzylisothioureide)benzene
To 100.0 g (0.33 mole) of imino(2-furylmethyl)-
2-(3-carbomethoxythiOureido) benzene and 50.0 g. (0.395
mole) of benzyl chloride in 275 ml. of dimethyl sul~oxide
is slowly added 15.0 ~ (0.375 mole) of sodium hydroxide
in 260 g. of water. The resulting mixture is stirred for
1/2 hour and the yellow precipitate is separated by
filtration and recrystallized from 800 ml of methylene
chloride-hexane (1:1) to give 91.1 g (70.1%) of 1-imino-
(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)-
benzene m.p. 112-114C.
Elemental Analysis for C21H19MOS:
Calc: C,64.10; H,4.87; N,10.68; 0,12.20; S,8.15
Found: C,64.22; H,4.83; N,ll.11; 0,12.29; S,8.24
EXAMPLE 95 - 1-Imino)2-furylmethyl)-2-(3-carbomethoxy-S-
butylisothioureido)benzene
To 5.0 g (0.0165 mole) of 1-imino(2-furylmethyl)-
2-(3-carbomethoxythioureido)benzene and 3.6 g (0.01975 mole)
of iodobutane in 80 ml. of N,N-dimethylformamide is added
0.7 g (0.0175 mole) of sodium hydroxide in 20 ml of water.
The resulting mixture is stirred for 1/2 hour and the
yellow precipitate that formed is separated by filtration,
washed with 50 ml of water and dried to give 3.4 g of
crude product, m.p. 86-7C. Recrystallization from
ether-hexane affords l-imino(2-furylmethyl)-2-(3-carbo~
methoxy-S-butylisothioureido)benzene m.p. 84-85C.
Elemental Analysis for C18H21N3O3S:
Calc.: C,60.15; H,5.89; N,11.69; 0,13.35; s,8.g2
Found: C,59.98; H,5.93; N,11.77; 0,13.83; S,8.90
- 57 -
75-78A
?SZ~
EXAMPLE 96 - 1-Imino(2-furylmethyl~2-(3-carbomethoxy-S-
methylisothioureido)benzene
_ .
A mixture of 3.03 g ~.01 mole) 1-imino(2-furyl- !
methyl)-2-(3-carbomethoxythioureido)benzene, 1.38 g (.01
mole) of potassium carbonate, and 1.42 g (.01 mole) of
methyl iodide in 50 ml of acetone is refluxed and stirred
for 1 hour. The suspension is allowed to stand at room
temperature for 24 hours and is vacuum filtered. The
filtrate is concentrated in vacuo and the residue orange
semi-solid is slurried in 50 ml of ether and allowed to stand
at room temperature for 24 hours. The suspension formed
is vacuum filtered and the filter cake of gold needles is
dried to afford 2.45 g (77% yield) of product, m.p. 97-
105C.
A sample of the product recrystallized from ether
affords l-imino(2-furylmethyl)2-(3-carbomethoxy-S-methyl-
isothioureido)benzene as a fluffy yellow solid, m.p. 94-
97C.
Elemental Analysis
for C15H15N33S: Calc: C,56.77; H,4.76; N,13.24; S,10.10
Found: C,57.22; H,4.84; N,13.60; S,10.43
- 58 - .
5Z1 76-78~
EXAMPLE ~7 - 1-Imino-(p-chlorophenyl)methyl-2-(~-carbo-
methoxy-S-methylisothioureido)-4-propylthio-
benzens
To a mixture o~ l-imino-(p-chlorophsnyl)-methyl-
2-(3-carbo~ethoxythioureido)-4-propylthiobsnzens (4.22 g.;
.01 mol) in acetone (25 ~1.) and water (1O ml.) there is
added 50~ aqueous sodium hydroxide (0.8 g.; .01 mol). The
mixture is stirred at room temparature for one hour and to
it there is added dimethyl sulfate (1.26 ~.; ,01 mol). The
reaction mixture is stirred at room temperature for one hour
and the precipitate collected and dried to afford l-imino-
tp-chlorophenyl)methyl-2-(3-carbomethoxy-S-methyli~othio-
ureido)-4-propylthiobenzene.
EXAMPLE ~98- 1-Iminophenylmethyl-2-(3-carbomethoxy-$-methyl-
isothioureido)-4-propylthiobenzene
To a solution of l-iminophenylmethyl-2-(3-carbo-
methoxythioureido)-4-propylth~obenzens (3.88 g.; .01 mol) in
acetone (40 ml.) and water (10 ml.) there is added calcium
hydroxide (0.74 g.; .01 mol). The mixture is stirred at room
temperature for 4 hours and then is added methy~ iodide
(1.42 g.; .01 mol). The .mixture is stirred at room tempera-
ture for 4 hours and the precipitate collected and dried to
afford l-iminophenylmethyl-2-(3-carbomethoxy-~-met hyli s ot hi o-
ureido)-4-propylthiobenzene.
EXAMPLE 99- 1-Iminophenylmethyl-2-(3-carbomethoxy-S-methyl-
isothi~lr- ~ -propylthiobenzere
To a solut,ion of l-iminophenylm~thyl-2-(3-carbo-
methoxythiourei.do~-4-propylthiobenzene (3.88 g.; .01 mol) in
dimethylformamide (40 ml.) and water (10 ml.) there is added
3o calcium hydroxide (0.74 g.; .01 mol). The mixture is stirred
at room temperature for four hours and to it there i~ added
dimethy~sulfate (1.26 g.). The mixture is stirred at rGom
- 59 -
76-78 l~
S21
temperature for four hours and the precipitate collected
and dried to afford l-iminophenylmethyl-2-~3-carbomethoxy-
S-methylisothioureido~-4-propylthiobenz~e.
EXAMPLE ~OC- l-Imino-(o-chlorophenyl)methyl-2~(3-carbo-
methoxy-S-methylisothioureido)-4-propylthio-
benzene
To a mixture of l-imino-(o-chlorophenyl)methyl-
2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.22 g.;
.Ol mol) in acetone (25 ml.) and water (lO ml.) there is
lO added 50~ aqueous sodium hydroxide (o.8 g.; .ol mol). The
mixture is stirred at room temparature for one hour and there
is then added dimethy~ sulfi~ (l.l g.; .Ol mol). The mixture
is stirred at room temperature for 3 hours and the precipi-
tate collected and dried to af~ord l-imino-(o-chlorophenyl)-
15 methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthio-
benzene.
EXAMPLE l~l- l-Iminophenylmethyl-2-(3-carbomethoxy-S-methyl-
isothioureido)-5-benzoylbenzene
To a solution of l-iminophen~lmethyl-2-(3-carbo-
20 methoxythioureido)-5-benzoylbenzene (4.33 g.; .Ol mol) in di-
methylformamide (50 ml.) and water (5 ml.) there is added
calcium hydroxide (0.74 g.; .Ol mol). The mixture i3 stirred
at 30C. for 2 hours and to it there is added dimethyl sulfite
(1.1 g.; .01 mol). The mixture is stirred at room te~perature
25 for 3 hours and the precipitate c~llected and dried to af~ord
l-iminophenylmethyl 2-(3-carbomethoxy-S-methylisothioureido)-
5-benzoylbenzene,
EXAMPLE 102- l-Imino-(p-chlorophenyl)methyl-2-(3-carbo-
~~ methoxy-S-methylisothioureido)-4-phenylthio-
~0 benzene
J
To a mixture of l-imino-(p-chlorophenyl)-methyl-
2-(3-carbomethoxythioureido)-4-phenylthiobenzene (4~56 ~.;
.Ol mol) in ~cetone (35 ml.) there is added 57%
~ 60 -
76-78 I`
110~5Zl
sodium 'nydride (0.42 g.; oOl mol) (oil dispersion).
The mixture is stirred at room temperature for one hour
and there is then added methyl iodide (1.42 g.; .01 mol).
The mixture is stirred at room temperature for one hour
and is poured into an excess of water. ~he suspension
is filtered and the precipitate dried to a~ford l-imino-
~p-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothio-
ureido)-4-phenylthiobenzene.
EXAMPLE 1,~3- 3-Imino-(o-chlorophenyl)methyl-4-(3-carbo-
methox~-S-meth.-Ylisothioureido)benzoPhenone
To a mixture of 3-imino-(o-chlorophenyl)methyl-
4-(3-carbomethoxythioureido)benzophenone (4.52 g.; .01 mol)
in 1,2-dimethoxyethane (50 ml.) there is added ~7~ sodium
hydride (0.42 g.; .01 mol) (oil dispersion). Tne mixture
is stirred at room temperature for one hour and there is
then added dimethyl sulfate (1.26 g.; .01 mol). The mix-
ture is stirred at room temperature for one hour and is
poured into an excess o~ water. The suspens-on is
filtered and the filter cake dried to afford 3-imino-(o-
chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido~
~enzophenone.
EXAMPLE lQ4- 3-Imino-(o-n~trophenyl)methyl-4-(3-carbome~hoxy-
S-methYlisothio~ureido)benzo~henone
To a mixture of 3-imino-(o-nitrophenyl)methJl-
4-(3-carbomethoxythioureido)benzophenonQ (4.62 g.; .01 mol)
in dimQthyl formamide (40 ml.) there is added 57~ sodium
hydride (0.42 g.; .01 mol) (oil dispersion). The mix.ure
is stirred at room temperature ~or one hour and to it
there is added dimethyl sulfite(l.l g.; .01 mol). The
3o mixture is stirred at room temperature for l-1/2 hours
and is poured into an excess o~ water. The suspension
- 61 -
76--78~ !
521
formed is vacu~m filtered and the filter caked dried to
afford 3-imino-(o-nitronhenyl)metnyl-4-(3-carbo~ethoxy-
S-methylisothioureido)benzophenone.
EXAMPLE 1~5- 3-Imino-(3,4-dichlorophenyl)methyl-4-(3-
carbomethoxy-S-msth~lisothioureido)benzophenone
To a mixture of 3-imino-(3,4-dichlorophenyl)-
methyl-4-(3-carbomethoxythioureido)benzophenone (4.86 g.;
.01 mol) in acetone (50 ml.) there is added calcium
hydride (0.42 g.; .01 mol). ~he mixture i3 r~fluxed
for one hour and then cooled to room temperature. To
the mixtllre is added methyl iodide (1.~2 g.; .01 mol).
The mixture is stirred at room temperature for one hour
and is poured into an excess of ice water. The suspension
formed is filtered and the filter cake dried to afford
3-imino-(3,4-dichlorophenyl)methyl-~-(3-carbome~hoxy-S-
methylisothioureido)benzophenone.
EX~MPLE lO~- 3-Imino-(4-methoxyphenyl)metnyl-4-(3-
carbomethox~ -meth~lisothioureido)benzoPhenone
To a mixture of 3-imino-(4 methoxyphenyl)methyl-
4-(3-carbomethoxythioureido)benzophenone (4.47 g.; .01 mol)
in 1,2-dimethoxyethane (50 ml.) there is added calcium
hydride (0.42 g.; .01 mol). The mixture is refluxed for
one hour and is cooled to room temperature. To the mixture
there is added dimethylsulfate (1.26 g.; oOl mol). The
mixture is stirred at room temperature for one hour and is
poured into an excess of ice water. The suspension formed
is filtered and the filter cake dried to afford 3-imino-
(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methyliso-
thioureido)benzophenone.
- 62 -
76-78~-\
S21
I
E ~PLE ~07- 3-Imino-(4-nitrophenyl)methyl-4-(3-carbo-
methox~-S-methvlisothioureido)benzophenone
To a mixture of 3-imino-(4-nitrophenyl)-
methyl-4-(3-carbomethoxythioureido)benzophenone (4.62 g.;
.01 mol) in acetone (50 ml.) there is added calcium
hydride (0.42 g.; .01 mol). ~he mixture is refluxed for
one hour and is cooled to room temperature. ~o the mixture
there is added dimethylslllfite (1~1 g.; .01 mol). The mix-
ture is stirred at room temperature for one hour and is
poured into an excess of ice water. The suspension fo-med
is filtered an~ the filter cake dried to afford 3-imino-
(4-nitrophenyl)methyl-~-(3-carbomethoxy-S metnylisothio-
ureido)benzophenone.
3X~LE1~8 - 1-Iminophenylmethyl-2-(3-carbomethoxy-S-
meth~lisothioureido~-4-PropYlthiobenzene
To a mixt~lre of 2-(3-carbomethoxy-S-methyl-
isothioureido)-~-propylthioaniline (3.13 g.; .01 mol) in
methanol (25 ml.), cooled to 5C., there is added benz-
aldehyde (1.06 g.; 0.1 mol). ~he mixture is stirred at
room temperature for one hour and is filtered. The filter
cake is dried to afford l-iminophenylmethyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propylthiobenzene.
EXAMPLE ~109- 1-Imino-(~-chlorophenyl)methyl-2-t3-carbo-
methoxy-S-methylisothioureido)-~-phenylthio-
aniline
To a mixture of 2-(3-carbomethoxy-S-methyliso-
thioureido)-~-phenylthioaniline (~.5~ g.; .01 mol) in
methanol (25 ml.), cooled to 5C., is added p-chlorobenz-
aldehyde (1.4 g.; .01 mol) followed by concentrated sulfuric
acid (3 drops). The mixture is stirred at 5C. for one
hour and is then vacuum filtered. The filter cake is
dried to afford l-imino-(4-chlorophenyl)methyl-2-(3-carko-
methoxy-S-methylisothioureido)-4-pllen~lthioaniline.
- 63 -
76-78
~ 5 21
EXAMPLE 110- 3-Imino-(4-nitrophenyl)~nethyl-4-(3-carbo-
mgthox~-~-methylisothioureido)benzophenone
To a mixture of 3-amino-4-(3-carbometho~y-S-
methylisothioureido)benzophenone (3.43 g.; .01 mol) in
be~zene (lO0 ml.) there i a added 4-nitrobenzaldehyde (1.5
g.; .01 mol). The mixture is re~luxed and stirred for 3
hours. Water of the reaction is rem~ved by a Dean-Sta~k
distillation receiver. ~he mixture is poured into an
excess of hexane ana the suspension formed is vacuum
filtered. The filter cake is dried to afford 3-imino-(4-
nitrophenyl)methyl-4-(3-carbomsthoxy-S-methylisothio-
ureido)benzophenone.
EXAMPLE 111- 3-Imino (4-methoxyphenyl)meth 1-~-(3-carbo-
methoxY-S-methylisothioureido~bsnzophenone_
To a mixture o~ 3-amino-4-(3-carbomethoxy-S-
mathylisothioureido)benzophenone (3.~3 g.; .01 mol) in
benzene (100 ml.) -there is added P-methoxybenzaldehyde
(1.36 g.; .01 mol~ and p-toluenes-ul~niC acid mono-
hydrate (0.1 g.). The mixture is refluxed and stirred for
3 hours. The water reaction is removed by a Dean-Stark
distillation receiver. The mixture is poured into an
excess of hexane and the suspension formed is filtered.
~he ~ilter cake is dried to afford 3-imino-(4-methoxy-
phenyl)methyl-4-(3 carbomethoxy-S-methyli~thioureido)-
benzophenone.
EXAMPLE 1l2- 1-Iminophenylmethyl-2-(3-carbomethoxy-S-
methylisothioureido)-~-_-propylsulfinyl-
benzene
, To a solution of l-iminophenylmethyl-2-(3-
3o carbomethoxy-S-methylisothioureido)-4-n-propylthiobenzene
(4.02 g.; .01 mol) in methylene chloride (50 ml.), cooled
to -5C., is added o5% of _-chloroperoxybenzoic acid
_ f~LI _
76-78~\
~ 5 21
(2.02 g.; .01 mol). The mixture is st.irred at -5C. for
30 minutes and is washed with aqueous sodium bicarbonate
solution~ The methylene dichloride is evaporated from the
organic solution to afford l-iminophenylmethyl-2-(3-
carbomethoxy-S-methylisothioureido)-~-n-propylsulfinyl-
benzene.
EXAMPLE 113- l-Iminophenylmethyl-2-(3-carbomethoxy-S-
- methylisothioureido~-4-_-prcpylsulfonylbe~zene
lo a solution of l-iminophenylmethyl-2-(3-
carbomethoxy-S-meth~Jlisothioureido)-~-jn-propylthiobenzene
~4.02 g.; .01 mol) in methylene chloride (50 ml. ), cooled
to -5C~, is added _-chloroperoxybenzoic acid (4.04 g.;
.02 mol). The mixture is stirred at room temperature
for 2 hours and is washed with aqueous sodium bicarbonate
solution. The methylens dichloride is evaporated from the
organic mixture to afford l-iminophenylmethyl-2-(3 carbo-
methoxy-S-methylisothioureido)-~-n-propylsulfonylbenzene.
EXAMPLE ~14- l-Iminopropyl-2-(3-Carbomethoxy-S-
methylisothioureido)-~-~ro~ylthiobenzene
Step A- l-Iminopropyl-2-(3-carbomethoxy-
thioureido~-4-Propvlthiobenzene
To a suspension of 2-(3-carbomethoxy-
thioureido)-~-propylthioaniline (2.99 g.; .01 mole) in
methanol (50 ml.), cooled to 5C., there is added propion-
aldehyde (0.6~ g.; .01 mole). The mixture is stirred at
5G. for 2 hours and the solution formed is stirred at
~oom temperatllre for l week. The s-~spension that forms is
vacuum filtered and the filter cake is washed with ether
and dried tc afford l-iminopropyl-2-(3-carbomethoxy-
3o thioureido)-~-propylthiobenzene (1.3 g.; 38.3%), m.p.
163-168 C. (dec.).
- 65 -
76-78
~ 5 2 ~
Elemental analysis for C15H21N302S2
Calc.~ C, 53.07; H, 6.24; ~J, 12.38
Foun~: C, 52.72; H, 6.32; N, 12.38
Step B - l-Iminopropyl-2-(3-carbomethoxy-
S-methylisothioureido)-~-propJlthio-
benzene
To a suspenslo~ o~ l-imino~ropyl-
2-(3-carbomethoxythioureido)-~-propylthiobe~zene ~1 g.;
.00295 mole~ in acetone (30 ml.) and water (L5 ml.) there
is added 50.8% aoueous sodium hydroxide (0.23 g.; ~00295
mole). The solution that forms is stirred at room
temperature f~r one hour and to it there is added met;~yl
iodide (0.~2 g.; .0029~ mole). The turbid solution formed
is stirred at room temperature for 30 minutes and is
poured in.o wa'er (500 ml.). The suspension for~ed is
s~irred at ro~m temperature ~or one hour an~is vacullm
filtered. The ~ilter cake is dried to afford l-imino-
propyl-2-(3-carbomethoxy-S-methylisothioureido)-~-
propylthiobenzene (0.85 g.; 81.5%) ? m.p 85-go~ ec.).
Elemental analysis for C16H23N302S2
Calc.: C, 5~.36; H, 6.56; N, 11.89
Fou~d: C, 53.96; H, 6.60; N, lL.63
EXAMPLE 115 - 1 Imino (4-methyl)phenylmethyl-2-(3carbo-
methoxy-S-methylisothioureido)-4-propyl-
thioben~ene
Step A - l-Imino(4-methyl)phenylmethyl-2-(3 carbo-
methoxythioureido-4-~ropylthiobenzene
To a suspension of 2-(3-carbomethoxythioureido)-4-
propylthioaniline (9.0 g; .03 mole) in methanol (100 ml),
cooled to 10C, there is added _-methylbenzaldehyde (3.6 g;
.03 mole). The mixture is stirred at lO~C for 1 hr. and
- 56 -
76-78A
llQ~S21
at room temperature for 18 hrs. The suspension that forms
is vacuum filtered and the filter cake is air dried to
afford l-imino(4-methyl)phenylmethyl-2-(3-carbomethoxy-
thioureido)-4-propylthiobenzene (10.75g; 89%), m.p. 135-
141C.
Elemental AnalysiS for C20H23N302S2
Calc: C, 59.82; H, 5.77; N, 10.46
Found: C, 59.32; H, 5.87; N, 10.75
Ste~ B - 1-Imino(4-methyl)phenylmethyl-2-(3~carbo-
~ methoxy-S-methylisothioureido)-4-propyl-
thiobenzene
To a suspension of l-imino(4-methyl)phenylmethyl-2-
(3-carbomethoxythioureido)-4-propylthiobenzene (4.02 g;
.01 mole) in acetone (60 ml) and water (20 ml) there is
added 50% aqueous sodium hydroxide (0.8 g; .01 mole). The
solution that forms within 10 min. is stirred at room
temperature for 50 min. and to it there is added methyl
iodide (1.42 g; .01 mole). The suspension that forms is
stirred at room temperature for 1 hr. and is vacuum filtered.
The filter cake is air dried to afford l-imino(4-methyl)-
; phenylmethyl-2-(3-carbomethoxy~S-methyl isothioureido)-4-
propylthiobenzene (3.6 g; 86.6%), m.p. 113-115C.
Elemental analysis for C21H25N32S2
Calc: 5, 60.69; H, 6.o6; N, 10.11
Found: C, 60.75; H, 6.29; N, 10.47
EXAMPLE 116 - 1-Imino-(4-methoxy)phenylmethyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propylthio-
benzene
Ste~ A - l-Imino-(4-methoxy)phenylmethyl-2-(3-
3 carbomethox~lthioureido)-~-~ro~vl~hiobenzene
To a suspension of 2-(3-carbomethoxy thioureido)-4-
propylthioaniline (9.0 g; .03 mole) in methanol (100 ml)
- 67 -
76-78A
llU~521
cooled to 10C, there is added _=anisaldehyde (4.o8 ~;
.03 mole). The mixture is stirred at 10C for 1 hr. and at
room temperature for 18 hrs. The suspension that forms is
vacuum filtered and the filter cake air dried to afford
1-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxythioureido)-
4-propylthiobenzene (9.9 g,;79%), m.p. 141-144C.
Elemental analysis for C20H23N303S2
Calc: C, 57.53; H, 5.55; N, 10.06
Found: C, 57.19; H, 5.67; N, 10.25
Step B - l-Imino-(4-methoxy)phenylmethyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propyl-
thiobenzene
To a suspension of l-imino-(4-methoxy)phenylmethyl-
2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.18 g;
.01 mole) in acetone (60 ml) and water (20 ml) there is
added 50~ aqueous sodium hydroxide (.38 g; .01 mole). The
solution that forms within 10 min. is stirred at room
temperature for 50 min. and to it there is added methyl
iodide (1.42 g; .01 mole). The suspension that forms is
stirred at room temperature for 1 hr. and is vacuum
filtered. The filter cake is air dried to af~ord l-imino-
(4-methoxy)phenylmethyl-2-(3-carbomethoxy-S-methylisothio-
ureido)-4-propylthiobenzene (2.3 g; 53%), m.p. 90-92.
Elemental analysis for C21H25N303S2
Calc: C, 58.44; H, 5.84; N, g.74
Found: C~ 58.38; H, 5.94; N, 9.91
EXAMPLE 117 - 1-Imino(4-nitro)phenylmethyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propylthio-
benzene
Step A - l-Imino-(4-nitro)phenylmethyl-2-(3-carbo-
methoxythioureido)-4-~ro~vlthioben~ene
.
To a suspension of 2-(3-carbometho~ythioureido)-4-
propylthioaniline (4.0 g; .013 mole) in methanol (35 ml)
- 68 -
76-7~A
l~U~521
there is added a solution of ~-nitrobenzaldehyde (2.0 g;
.013 mole) in methanol (35 ml). The mixture is stirred at
room temperature for 1 hr. and is vacuum filtered. The
filter cake is washed with methanol and dried to afford
1-imino(4-nitro)phenylmethyl-2-(3-carbomethoxythioureido)-
4-propylthiobenzene (5.3 g; 94%), m.p. 198-200C.
Elemental anal~sis for Cl9H20N44S2
Calc: C, 52.76; H, 4.66; N, 12.95; S, 14.83
Found: C, 52.85; H, 4.79; N, 13.39, S, 14.84
Step B - l-Imino-(4-nitro)phenylmethyl-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propyl-
t,hio~nzene
... ........ ~
A mixture of l-imino-(4-nitro)phenylmethyl-2-(3-
carbomethoxythioureido)-4-propylthiobenzene (4.3 g; .01 mole)
acetone (50 ml), water (25 ml) and 50% aqueous sodium
hydroxide (o.8 g; .01 mole) is stirred at room temperature
for 15 min. and is cooled to 12C. To the mixture there
is added methyl iodide (1.4 g; .01 mole) and it is stirred
at 13C to 20C for 2 hrs. The suspension that forms is
vacuum filtered and the filter cake is washed with acetone
and dried to afford l-imino(4-nitro)phenylmethyl-2-(3-
carbomethoxy-S-methylisothioureido)-4-propylthiobenzene
(3.5 g; 78%), m.p. 135-137C dec.
Elemental analysis for C20H22N404S2
Calc: C, 53.79; H, 4.97; N, 12.55; S, 14.36
Found: C, 53.39; H, 4.97; N, 12.60; S, 14.69
EXAMPLE 118 - 1-Imino-(2-furylmethyl)-2-(3-carbomethoxy-S-
methyl~sothioureido)-4-propylthiobenzene
Step A - l-lmino-(2-furylmethyl)-2-(3-carbomethoxy-
thioureido)-4-~rop~lthiobenzene
To a suspension of 2-(3-carbomethoxythioureido)-4-
propylthioaniline (6~0 g; .02 mole) in methanol (200 ml),
- 69 -
76-78A
SZl
cooled to 10C there is added 2-furfuraldehyde (1.92 g,
.02 mole). The mixture is stirred at 10C for 1 hr. and
at room temperature for 18 hrs. The suspension formed is
vacuum filtered and the filter cake is air dried to afford
1-imino(2~furylmethyl)-2-(3-carbomethoxythiouriedo)-4-propyl-
thioaniline (5.6 ~; 74%), m.p. 131-,33C.
Elemental analysis for C17H19N303S2
Calc: C, 54.09; H, 5.07; N, 11.13
Found: C, 53.68; H, 5.11; N, 11.13
Step B - l-Imino-(2-furylmethyl)-2-(3-carbomethoxy-
S-meth,ylisothioureido)-4-propylthiobenzene
To a suspension of l-imino-(2-furylmethyl)-2-(3-
carbomethoxythioureido)-4-propylthiobenzene (3.77 g, .01
mole) in acetone (45 ml) and water (15 ml) there is added
5% aqueous sodium hydroxide (0.79 g; .01 mole). ~ithin
15 min. after addition a solution forms and is stirred at
room temperature for 30 min. To the solution there is
added methyl iodide (1.42 g; .01 mole). The mixture is
stirred at room temperature for 1-3/4 hrs. and the sus-
pension that forms is vacuum filtered. The filter cake is
air dried to afford l-imino-(3-furylmethyl)-2-(3-carbo-
methoxy-S-methylisothioureido)-4-propylthiobenzene (2.65 g;
67.7~), m.p. 96-98C.
Elemental analysis for 518H21N33S2
Calc: C, 55.22; H, 5.41; N, 10.73
Found: C, 54.71; H, 5.39; N, 10.51
--- - - . .
- 70 -
75-78A
5Z~
.
.. . . . .. . ... . . . . . .. . . . . .. . .. . ...
EXAMPLE 119
When the procedures o~ the above examples are
~ollowed and by employin~ known starting diamine precursors,
the following products may be ob~ained:
3-iminophenylmethyl-4-(3-carboethoxy-S-methylisothioureido)-
benzophenone;
3-imino(p-chloro)phenylmethyl-4-(3-carbopropoxy-S-methyl-
isothioureido)benzophenone;
l-iminophenylmethyl-2-(3-carbo-isopropoxy-S-methylisothio-
ureido)-4-propylthiobenzene;
l-iminophenylmethyl-2-(3-carbobutoxy-S-allylisothioureido)-
4-phenylthiobenzene;
3-iminophenylmethyl-4-[3-carbo-(2-methoxy)ethoxy-S-methyl-
isothioureido]benzophenone;
l-iminophenylmethyl-2-[3-carbo-(2-methoxy)ethoxy-S-methyl-
10 i30thioureido]-4-propylthiobenzene;
3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)-
4'-chlorobenzophenone;
3-imino-(~-chlorophenyl)methyl-4-(3-carbomethoxy-S-allyl-
isothioureido)-4'-fluorobenzophenone;
.... . ~ . . ..
.. . . ... .. ..
3-iminophenylmethyl-4-(3-carbomethoxy-S-butylisothioureido)-
4'-methylbenzophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-benzylisothioureido)-
4'-methoxybenzophenone;
3-imino-(o-chloro)phenylmethyl-4-(3-carbomethoxy-S-methyl-
15 isothioureido)-3'-trifluoromethylbenzophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothio-
ureido)propiophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-allylisothioureido)-
butyrophenone;
3-imino-p-nitrophenylmethyl-4-(3-carbomethoxy-S-butylisothio-
ureido)valerophenone;
l-cyclopropylcarbonyl-3-iminophenylmethyl-4-(3-carbomethoxy-
S-methylisothioureido)benzene;
1-cyclopentylcarbonyl-3-imino-(~-chloro)phenylmethyl-4-
(3-carbomethoxy-S-butylisothioureido)benzene;
.. _ , . . . . . . . .. . . . . .
- - 76-78 A
1106~521
1-(2-thienyl) -3-im no-~-msthylphenyl~ethyl-4-(3-carbo-
methoxy-S-methylisothioureido)benzene;
l-imin~ henylmethyl-2-(3-carbomethoxy-S-methylisothio-
ureido~-4-(4-cyanophenylthio)benzene;
1-imino~henylmethyl-2-(3-carbomethoxy-S-butylisothio-
ureido)-4-(3-cyanophenJlthio~benzene;
l-imino~henylmethyl-2-(3-carbomethoxy-S-butylisothio-
ureido)-4-(4-methylthiophenylthio)benzene;
l-iminophenylmethyl-2-(3-carbometho~y-S-m3thylisothio-
ureido~-4-(3-methylthiophenylthio)benzene;
l-imino-(~-c~lorophenyl)meth~1-2-~3-carbomethoxy-S-methyl-
isothioureido~-4-(4-acetylphenyl~hio)benzens;
l-imino-(p-chlorophenyl)methyl-2-(3-carbomethoxy-S-allyl-
isothioureido)-4-(4-metho~ycarbonylphenylthio)benzene;
1-iminophenylmet~yl-2-(3-carbomethoxy-S-methylisothio-
ureido~-4-(4-acetylaminophenyl~benzene;
l-imino henylmsthyl-2-(3-carbometh~xy-S-butylisothio-
ureido~-4-(4-phen~xyphenylthio~benzene;
l-imino henylmethyl-2-(3-carbometh~xy-S-methylisothio-
ureido~-~-t4-cyanophenylsulfin~Jl)benzene;
l-imino-~-chlorophenyl)~ethyl-2-(3-carbomethoxy-S-butyl-
isothioureido)-4-(4-acetylphenylsulfinyl)benzene;
l-iminophenylm_thyl-2-(3-carbomethoxy-S-methylisothio-
ureido~-~-(4-cyanophsnylsulfonyl)benzene;
1-imino-(~-chlorophenyl)m~thyl-2-(3-carbomethox-r-S-methyl-
isothioureido)-4-(4-acetylphenylsulfonyl)benzene;
-imino-(P-chlorophenyl)methyl-2-(3-carbomethoxy-s-moth~
isot.hioureido)-4 (phenylsulfinyl)benzene;
l-imino-(p-cnloro~henyl~msthyl-2-(3-caLbomethoxy-s-meth
isothioureilo)-~ (phenylsulfo.~yl)benzene;
l-imino-(~-chlorophenyl)~ethyl-2 (3-carbomethoxy-S-methrl-
isothioureido)-5-(4-acetylphenylsulfonyl)benzene;
l-imino-(o-chloro~henyl)methyl-2-(3-carbomethoxy-S-methyl-
isothioureido 5-~4-cyanophenylsulfonyl)benzene;
1-imino~hen~Jlmethyl-2-(3-carbomethoxy-S-methylisothio-
ureido)-5-~4-acetylphenylsulfinyl)benzene;
l-imin~ henylmethyl-2-(3-carbomethoxy-S-methylisothio-
ureido~-5-(4-cyanophenylsulfinyl)benzen^;
,.1~ ~
. x~ ,
76-78
1 10 ~ 5 21
l-iminophenylmethyl-2-(3-carbometho~y-S-methylisothio-
ureido)-5-phenoxysul~onylbenzene;
l-(imino-p-chlorophenylmethyl)-2-(3-carbomethoxy-~-
methylisothioureido)-5-(~-cnlorophenox~sulfonyl)benzene;
1-(imino-p-chlorophenylmethyl)-2-(3-carbomethoxy-s-but
isothioureido-5-(3-chlorophenoxysulfonyl~benzene;
l-iminophenylmethyl-2-(3-carbomei,hoxy-S-benzylisothio-
ureido-5-(2 chlorophenoxysulfonyl)benzene;
l-~imino-o-chlorophenylmethyl)-2-(3-carbomethoxy-S-allyl-
isothioureido)- 5-(3,5-dichlorophenoxysulfonyl)benzene;
l~~imino-P-nitrophenylmet'nyl)-2-(3 carbomethoxy-S-methyl-
isothiourei~o)-5-(4-methoxyphenoxysul~onyl)benzene;
l-(imino-~-methoxyphenyl)-2-(3-carbomethoxy-S-methyliso-
thiourei~o)-5-(3-cyanophenoxysulfonyl~benzene;
1-iminophenyl-2-(3-carbomethoxy-S-methylisothiourei~o)-5-
(3-trifluoromethylphenoxysulfonyl~benzene;
l-i~inophenylmethyl-2-(3-~arbomethoxy-S-methylisothio-
ureido~-5-phenylsulfonyloxybenzene;
l-imino-(~-chlorophenyl)methyl-2-(3-carbomethoxy-S-allyl-
isothioureido)-5-(4-chlorophenyl)sulfonyloxybenzene;
l-imino-(o-chlorophenyl)methyl-2-(3-carbo~ethoxy-S-b~tyl-
isothiourei.~o)-5-(3-chlorophenyl)sulfonyloxybenzene;
l-iminophenylmethyl-2-(3-carbomethoxy-S-butylisothio-
ureido)-5-(3,5-dichlorophenyl)sulfonyloxybenzene;
1-imino-(~-nitrophenyl)methyl-2-(3-carbomethoxy-S-benzyl-
isothioureido)-5- (4-methylphenyl~sulfonyloxybenzene;
-imino-(P-methoxyphenyl~methyl-2-(3-carbomethoxy-s-a
isothioureido)-5- (3-trifluorophenyl)sulfonyloxybenzene;
l-iminophenylmethyl-2-t3-carbomethoxy-S-methylisothio-
ureido)-5-(4-methoxyphenyl)sulfonyloxybenzene.
Examples of other X substituents on known
diamines ~nclude 4-and 5-propoxy; 4- and 5-phenoxy; 4-
and 5-(pyrid-2-yloxy); 4-(~-chlorophenoxy); 4-(trifluoro-
methylphenoxy); 5- (3-chloropropoxy); 5-(2-phenylethoxy);
5- (3-phenylprop-2-en-l-yloxy); 5- (4-methylphenoxy); 5-(3-
methylphenoxy); 5- (2-methylphenoxy); 5-(3-methylthio-
phenoxy); 5- (propargylthio); 5-(but-3-en-1-yl-thio);
~o-~ol l
l~OQSZl
5-(but-3-en-1-yl-sulfinyl); 5-(but-3-en-1-yl-sulfonyl);
5-(b3nzylthio); 5-(benz~Jlsulfin~Jl); 5-(thiazol-2-yl-
thio); 5-(pyrid-2-yl-thio~; 4-pyrimidin-2-yl-thio);
5-(thien-2-yl-thio); 5-(fur-2-yl-t~io); 5-(3-c;~loro-
propylthio); 4-(3-chloropropylthio); 4-(3-chloroprop-2-
en-l-yl-th o); 4-(2-cyanoethylthio); 5-(2,3-dichloro-
propyl-2-en-1-yl-thio) and the like.
These diamine precursors can be found in
U. S. Pat. Nos. 3,657,267; 3,929,823; 3,929,824; 3,935,209;
3,98~,561; 3,993,768; 3,996,368; 3,996,369; ~,002,640;
French Pat. Nos. 2,248,037; 2,270,861 and Netherlands Pat.
No. 4,701,797.
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