Note: Descriptions are shown in the official language in which they were submitted.
~485~9
Certain substituted s~triazolo[3,4-b~benzothiazoles
(hereinafter referred to as "triazolobenzothiazole compounds")
are employed for the control of plant pathoqens, including
fungal organisms and bacterial organisms. ~hus, the tri~
azolobenzothiazole compounds can be employed for the control
of such organisms as crown gall, rice blast, leaf rust,
powdery mildew, anthracnose, and the like. The compounds
are particularly suited for the control of fungal organisms,
and give particularly good results in the control of rice
blast. Belgium patent No. 789,918 describes their prepara-
tion by cyclodehydration of 2-acylhydrazinobenzothiazole
compounds with polyphosphoric acid.
It is a purpose of this invention to provide new
intermediate 4-(o-halophenyl)-1,2,4-triazole-3-thiol com-
pounds which are utilized in the preparation of such tri-
azolobenzothiazole compounds as described in copending
Canadian application Serial Number 221,381, filed March 6, 1975.
This invention relates to a novel 4-(o-halophenyl)-
1,2,4-triazole-3-thiol compound of the formula
R~r (I}I):
1 R ~ N
wherein, in the foregoing formulae, ~ is hydrogen, Cl-Cll al~yl,
cyclopropyl or trifluoromethyl; Rl is hydrogen, bromo, chloro
or fluoro; R2 and R3 are independently hydrogen, Cl-C3 alkyl,
Cl-C3 alkoxy, bromo, chloro, fluoro or trifluoromethyl with the
- 1 -
'
~)485f! 9
limitation that at least one of R2 and R3 is hydrogen; X is
bromo, chloro or fluoro; and subject to the further limitation
that when Rl is halogen, R is other than hydrogen and R2 is
hydrogen.
The term "Cl-Cll alkyl" represents branched or
straight-chain alkyl groups of from 1 to 11 carbon atoms.
Exemplary of such straight-chain alkyl groups are methyl,
propyl, pentyl, hexyl, octyl, and decyl. Exemplary of the
branched chain alkyl groups are isopropyl, t-butyl, isopentyl,
neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl,
and 2,5-dimethyl-4-ethylheptane. The term '`Cl-C3
alkyl" includes methyl, ethyl, propyl and isopropyl. The
term ~Cl-C3 alkoxy represents ether groups such as methoXy,
ethoxy, propoxy, and isopropoxy. I~here the term "halo" or
"halogen" is employed, it refers only to bromine, chlorine
and fluorine.
The compound of this invention is reacted with
at least a molar equivalent of base in a substantially an-
- hydrous amide solvent at a temperature of 60C. - 200C.
2~ to produce compounds of the formula (I)
R~ _ ~ ~ S
R~ ~ N~ lN~
Rl ~ ~
All the starting materials and intermediates re-
quired in the instant invention are prepared by methods
known to the art. The l-acylhydrazine compounds represented
by the formula
- 2 -
1048S~9
o
NH2NHC-R (IV)
are prepared by reacting hydrazine with the appropriate
acid derivatives such as the acid chloride, the anhydride
or the ester. Isee Organic Reactlons, Vol. 3, N.Y., Wiley,
1946, pp. 366-369].
The o-halophenylisothiocyanate compounds rep- ,
resented by the formula
X
R~ _~N=C=S
R2 R1 ( ) -,
are prepared by reacting the appropriate o-haloanilines with
dimethylaminothiocarbamoyl chloride in an aromatic solvent ~;
[see J. Org. Chem., 30, 2465 (1965)~.
The intermediate l-acyl-4-(o-halophenyl)-3-
thiosemicarbazide compounds, are prepared by reacting the
aforementioned starting materials in an aprotic solvent at
elevated temperatures. The thiosemicarbazides in turn are
converted to the triazolothiol compounds by reaction with
aqueous base, as described in Ind. J. Chem., 5(9),
397 (1967): Chem. Abst. 68, 59501w (1968). The reaction
sequence leading to the triazoloth,iol compounds is outlined
below.
- 3 -
.. . .
1048SQ9
`J
X o
R3~N=C=S ~Nl~2NHC-R aprot i c~
>=~ so I vent
Rz~ Rl (V) (IV)
R~NHCNHHHC-R (II) ( )
R2 R1 R3
R2 _~_X
' ~ ~ (III~
After initial thiosemicarbazide formation a double intramole-
cular cyclization is effected to produce the benzothiazole:
(1) a cyclodehydration to provide the triazolothiol and
(2) an aromatic halogen displacement to provide the desired
benzothiazole compound. The cyclodehydration provides a 4-
(o-halophenyl)-1,2,4-triazole-3-thiol which undergoes aromatic
halogen displacement by thiol anion generated in the presence
of base to provide the instant triazolobenzothiazole compound.
In the halogen displacement reaction by thiol anion,
Rl is equivalent to X when both are bromo, chloro or fluoro.
One of Rl or X is displaced to provide a 5-bromo-, 5-chloro-
or 5-fluorotriazolobenzothiazole. When Rl and X are
separately bromo, chloro or fluoro, mixtures of 5-chloro-,
5-bromo- and 5-fluorotriazolobenzothiazoles are obtained.
Such mixtures are separable by methods such as fractional
crystallization or chromatography. The process operates
when Rl or X is iodo; however, the required o-iodophenyliso-
thiocyanate startin~ materials are less readily available.
They are more difficult to prepare and render the process
less economical.
-- 4
.
.
-
~)48S~9 ::
V
In general, it appears that electronegative phenyl
substituents facilitate halog~n displacement as evidenced
by high product yields and short reaction times. Electron
donating substituents such as methyl ten~ to retard halogen
displacement resulting in increased reaction times and pro-
duction of dimeric side products.
The l-acyl-4-(o-halophenyl)-3-thiosemicarbazide
compounds (Compound II) are prepared by reacting molar
equivalents of an acylhydrazine (Compound IV) and an
o-halophenylisothiocyanate (Compound V) in a substantially
anhydrous aprotic solvent at a temperature from about
60C. to about 100C for about 24 hours. A substantially
anhydrous aprotlc solvent refers to a type of solvent :
which does not offer or accept protons but which might
possibly still contain trace amounts of water. Exemplary
of the aprotic solvents employed are,benzene, dichloroethane,
; dioxane, the dimethylether of ethylene glycol, tetrahydro-
furan (TIIF), and the like. TIIF is a preferred solvent for the
preparation of the thiosemicarbazide compounds. The thio-
semicarbazide product is recovered by evaporation of the
solvent and purified by conventional methods.
The 4-(o-halophenyl)-5-substituted-1,2,4-triazole-~-
thiol compounds are prepared from the corresponding thio-
semicarbazide compounds by cyclodehydration with a molar
! equivalent of an alkali metal hydroxide in an aqueous or dilute
. :
Cl-C3 carbinol medium. Exemplary of suitable carbinol sol-
vents are methanol, ethanol, propanol and isopropanol. The
preferred cyclodehydration conditions are aqueous sodium
hydroxide and steam bath temperature. If desired, the tri-
azolothiol salt can be obtained by evaporation of the solvent
.
. - . , .
v 1~8s~l9
and heated in an amide solvent to provide the triazolo-
benzothiazole compounds. ~sually, however, the basic
mixture is acidified and the insoluble triazolothiol com-
pound is recovered for use in the process.
It will be noted that it is not neces`sary to isolate
the intermediate triazolothiols to operate the process.
Solvents which may be employed in the instant
process are commonly used tertiary amide solvents, which
O are unreactive with the starting materials and product. A
substantially anhydrous tertiary amide solvent can be used.
The term "substantially anhydrous" means that the presence
of small amounts of water can be tolerated in the solvent.
Generally the amide solvent can be "dried" in situ by using
one to ten percent excess of base to react with the residual
water. Exemplary of the amide solvents which are employed
are N,N-dibutylacetamide, dimethylacetamide (DMAC), dimethyl-
formamide (DMF), and N-methyl-2-pyrrolidone. The higher
amide solvents are effective because of their higher
O boiling temperatures. For reasons of availability and ease
of removal, DMAC and DMF are preferred solvents.
In general, any base which is strong enough to gen-
erate a triazolothiol anion is suitably employed in the in-
stant process. Although a molar equivalent of base is
~ sufficient, the base serves a dual function. It participates
; ~1) in triazolothiol formation and (2) in the intramolecular
displacement of halogen by thiol anion. In addition to the
lithium alkyls such as methyl lithium and butyl lithium,
suitable bases include the alkoxides, amides, carbonates,
~ IO hydrides and hydroxides of the alkali metals. ~mong these are
; 6
10485~9
lithium ethoxide, potassium t-butoxide, and sodium methylate.
The carbonates and hydroxides of lithium, sodium, potassium,
cesium and rubidium can be used. The preferred bases which
can be employed in the process of this invention are lithium
amide, sodium amide, potassium amide, sodium-hydride, and
potassium hydride.
The instant process is operated at a temperature
range from about 60~C. to about 200C. When the process is
operated with the acylhydrazine and isothiocyanate compounds,
an induction period at a temperature of about 60C. to about
100C. for about 24 hours is employed to generate the 1-acyl-4-
(o-halophenyl)-3-thiosemicarbazide intermediate ln situ. After
the induction period, a molar equivalent of the preferred sodium
hydride is added and the reaction is completed at a temperature
of about 160C, the boiling temperature of the` preferred DMF
solvent. When the thiosemicarhazide or triazolothiol com-
, pound is employed in the process, it is dissolved in the DMF
a molar equivalent of the preferred sodium hydride is added
and the reaction mixture is brought to reflux temperature for
~ 20 a period of time sufficient to complete the reaction.Generally, the process is completed within 24 hours or less
at a temperature between 60C. and 100C. Halogen displacement
by thiol anion is influenced by the nature of the phenyl sub-
~; stituent groups. When R2 and R3 are electron donating groups
such as Cl-C3 alkyl, halogen displacement is retarded, thereby
requiring extended reaction times.
Illustratlve of the 4-(o-halophenyl)-5-substituted-
1,2,4-triazole-3-thiol compounds (Compound III) which can be
employed in the process of this invention are the following:
7 _
~":
:
35~9
4-(2-chlorophenyl)-1,2,4-triazole-3-thiol
4-(2-chlorophenyl)-5-methyl-1,2,4-triazole-3-thiol
4-(2-chloro-5-trifluoromethylphenyl)~5-methyl-
1,2,4-triazole-3-thiol
4-(2,4-dichlorophenyl)-5-methyl-1,2,4-triazole-3-
thiol
4-(2-chloro-4-methylphenyl)-5-methyl-1,2,4-triazole-
3-thiol
4-(2,6-dichlorophenyl)-5-methyl-1,2,4-triazole-3-
thiol
4-(2-chloro-5-methylphenyl)-5-methyl-1,2,4-triazole-
3-thiol
4-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-
triazole-3-thiol
5-propyl-4-(2-chloro-5-trifluoromethylphenyl)-1,2,4-
triazole-3-thiol
4-(2-chlorophenyl)-5-cyclopropyl-1,2,4-triazole-3-
thiol
5-cyclopropyl-4-(2,6-dichlorophenyl)-1,2,4-triazole-
3-thiol
4-(2-chlorophenyl)-5-trifluoromethyl-1,2,4-triazole-
3-thiol
4-(2,6-dichloro-4-propoxyphenyl)-5-trifluoromethyl-
1,2,4-triazole-3-thiol
4-(2-chloro-5-ethoxyphenyl)-5-ethyl-1,2,4-triazole-
: 3-thiol
. 4-(2-bromo-6-fluoro-5-methylphenyl)-5-butyl-1,2,4-
triazole-3-thiol
5-isopropyl-4-(2,4,6-trichlorophenyl)-1,2,4-triazole-
3u 3-thiol
': '
; 8
11~)485(3 9
4-(2-chloro-6-fluorophenyl)-5-nonyl-1,2,4-triazole-
3-thiol
4-(2-bromo-6-fluoro-5-methoxyphenyl)-S-propyl-1,2,4-
triazole-3-thiol
4-(2,6-dichloro-4-trifluoromethylphenyl)-S-trifluoro-
methyl-1,2,4-triazole-3-thiol
4-(2-chloro-6-fluoro-5-trifluoromethylphenyl)-S-
cyclopropyl-1,2,4-triazole-3-thiol
Illustrative of the triazolobenzothiazole compounds
(Compound I) provided by this invention are the following:
s-triazolo~3,4-b]benzothiazole
3-methyl-s-triazolo[3,4-b]benzothiazole
7-chloro-3-methyl-s-triazolo[3,4-b]benzothiazole
5-chloro-3-methyl-s-triazolo[3,4-b]benzothiazole
3,7-dimethyl-s-triazole[3,4-b]benzothiazole
3-heptyl-s-triazolo[3,4-b]benzothiazole
3-methyl-5-trifluoromethyl-s-triazolol3,4-b]benzo-
thiazole
3,6-dimethyl-s-triazolol3,4-b]benzothiazole
6-methoxy-3-methyl-s-triazolol3,4-b]benzothiazole
3-propyl-6-trifluoromethyl-s-triazolo[3,4-b]benzo-
thiazole
3-cyclopropyl-s-triazolo[3,4-b]benzothiazole
S-chloro-3-cyclopropyl-s-triazolo[3,4-b]~enzo-
. . .
.. ~ thiazole
~ 3-trifluoromethyl-s-triazolo[3,4-b]benzothiazole
.~ .
5-chloro-7-propoxy-3-trifluoromethyl-s-triazolo-
. [3,4-b]-benzothiazole
- 3-ethyl-6-ethoxy-s-triazolo[3,4-b]benzothiazole
,'~ - g_
,~ .
~ , : . . '
" 1048S~9
5-fluoro-6-methyl-3-butyl-s-triazolo13,4-b]benzo-
thiazole
5,7-dichloro-3-isopropyl-s-triazolo[3,4-b]benzo-
thiazole
5-fluoro-3-nonyl-s-triazolo[3,4-b~benzothiazole
5-fluoro-6-methoxy-3-propyl-s-triazolo[3,4-b]benzo-
thiazole
5-chloro-3,7-bis(trifluoromethyl)-s-triazolo[3,4-b]-
benzothiazole
3-cyclopropyl-5-fluoro-6-trifluoromethyl-s-triazolo-
benzothiazole
The following examples further illustrate the
preparation of the starting materials, intermediates and
compounds of our invention.
(II) Prepara_ion of Triazoles,_Startinq Materlals
Example A
One and one-tenth grams (20 mmoles) of potassium
hydroxide were dissolved in 50 ml. of water. l-Formyl-4-(2-
fluorophenyl)thiosemicarbazide, 3.5 g. (16.5 mmoles), was -
dissolved in the basic solution by warming on the steam
bath until solution was completed. The heating was
. ' .
-- 10 -- , ,
. .
1¢~48509
V
continued for one hour. The cooled reaction mixture was
poured into a dilute solution of hydrochloric acid. The
insoluble product was recovered from the acidic solution by
filtration. The product was washed with water, collected and
dried. The yield was 2.5 g. of 4-(2-fluorophenyl)-1,2,4-
triazole-3-thiol, m.p. about 166-167C.
Analysis: C8H6FN3S MW 196
Calc: C, 49.22; H, 3.1~; N, 21.53
Found: C, 49.09; H, 3.13; N, 21.37
Example E
The following 4-(2-halophenyl)-1,2,4-triazole-3-
thiols were prepared from the appropriately substituted
thiosemicarbazides by cyclization in aqueous or alcoholic
base by the method of Example A
4-(2-chlorophenyl)-1,2,4-triazole-3-thiol, m.p.
about 195 196C.
Analysis: C8H6ClN3S MW 211.5
Calc: C, 45.39; H, 2.96; N, 19.85
Found: C, 45.48; H, 3.10; N, 19.70
4-(2-chlorophenyl)-5-methyl-1,2,4-triazole-3-thiol, -
m.p. about 217-219C.
Analysis: CgH8ClN3S MW 225
Calc: C, 47.89; H, 3.57; N, 18.62
Found: C, 47.73; H, 3.64; N, 18.39
4-(2,4-dichlorphenyl)-5-methyl-1,2,4-triazole-3-
thiol, m.p. about 248-253C.
Analysis: CgH7C12N3S MW 260
Calc: C, 41.55; H, 2.71; N, 16.15
Found: C, 41.57; H, 2.81; N, 16.37
4-(2-chloro-4-methylphenyl)-5-methyl-1,2, 4-tria201e-
., .
- 1~485Q9
~J
3-thiol, m.p. about 243-244C.
Analysls: CloHloClN3S MW
Calc: C, 50.10; H, 4.20; N, 17.53
Found: C, 50.23; H, 4.24; N, 17.73
4-(2-chloro-5-methylphenyl)-5-methyl-1,2,4-tri-
azole-3-thiol, m p. about 229-231C.
Analysis: CloHloClN3S MW 239
Calc: C, 50.10; H, 4.20; N, 17.53
Found: C, 49.98; H, 4.27; N, 17.40
4-(2,6-dichlorophenyl)-5-methyl-1,2,4-triazole-3-
thiol, m.p. about 240-242C
y : CgH7C12N3S MW 260
Calc: C, 41;55; H, 2.71; N, 16.15
Found: C, 41.32; H, 2.80; N, 15.98
4-(2-chloro-6-methylphenyl)-1,2,4-triazole-3-thiol,
m.p. about 237C-240C
Analysis: CgH8ClN3 MW 225
Calc: C, 48.00; H, 3.55; N, 18.66 -~
Found: C, 48.00; H, 3.32; N, 18.62
'0 4-(2-chloro-5-trifluoromethylphenyl)-5-methyl-i,2,4-
triazole-3-thiol, m.p. about 208-209C.
Analysis: CloH7ClF3NS MW 293
Calc: C, 40.90; H, 2.40; N, 14.31
Found: C, 40.95; H, 2.42; N, 14.27
4-(2-chlorophenyl)-5-hep~yl-1,2,4-triazole-3-thiol,
m.p. about 150-157C.
Analysis: C15H20ClN3S MW 309
Calc: C, 58.14; H, 6.51; N, 13~56
Found: C, 57.95; H, 6.33; N, 13.79
~0 4-(2,5-dichlorophenyl)-5-methyl-1,2,4-triazole-3-
- 12 -
' :
.. , ~ . . . .
-
~48S~;!!g
thiol, m.p. about 248-250C.
Analysis: C9H7cl2N3s MW 260
Calc: C, 41.55; H, 2.71; N, 16.15
Found: C, 41.85; H, 3.00; N, 16.40
(III) Preparation of Triazolobenzothiazoles~ Final Products
Example 1
Five grams (19 mmoles) of 4-(2,4-dichlorophenyl)-
5-methyl-1,2,4-triazole-3-thiol were dissolved in 100 ml. of
DMF. One gram (20 mmoles) of sodium hydride, as a 50%
10 mineral oil dispersion, was added portionwise to the stirred
reaction mixture. The mixture was refluxed for 24 hours and
then poured into 600 ml. of water. The aqueous mixture was
extracted wlth n-hexane to remove the mineral oil. The
aqueous phase was extracted with ethyl acetate overnight by
means of a liquid-liquid extractor. The ethyl acetate was
dried (MgSO4) and evaporated ln vacuo to a residue. The
residue was washed with toluene and the crystalline product
was collected by filtration. The yield was 1.9 g. (45 percent)
of 7-chloro-3-methyl-s-triazolo[3,4-b]benzothiazole, m.p.
about 186-188C. A second crop, 1.6 g., m.p. about 185-188C.,
was recovered from the aqueous phase.
Analysis: CgH6ClN3S MW 224
Calc: C, 48.33; H, 2.70; N, 18.79
Found: C, 48.32; H, 2.89; N, 18.96
When the appropriate 4-(o-halophenyl)-5-substituted-
1,2,4-triazole-3-thiol was substituted for the 4-(2,4-dichloro-
phenyl)-5-methyl-1,2,4-triazole-3-thiol in the above procedure,
there were obtained the following products:
30 3-methyl-s-triazolo~3,4-blbenzothiazole, melting at
about 153-154C.
13 -
~485Q9
s-triazolo[3,4-b]benzothiazole, melting at about
175-176C.
6-chloro-3-methyl-s-triazolo[3,4-b]benzothiazole,
melting at about 264-266C.
S-chloro-3-methyl-s-triazolo[~,4-b]benzothiazole,
melting at about 186-188C. -~
3,7-dimethyl-s-triazolo[3,4-b]benzothiazole, melting
at about 176-177C.
3,6-dimethyl-s-triazolo13,4-b~benzothiazole, melting
at about 203-2~7C.
3-methyl-6-trifluoromethyl-s-triazolo[3,4-b]benzo-
thiazole, melting at about 181-183C.
3-heptyl-s-triazolo[3~4-b]benzothiazole~ melting
at about 82-84C.
~. ~
.
.
.'.'` ~ .
;;,
- 14 -
. .
: .
-.
