CA1048509A - 4-(0-halophenyl)-1,2,4-triazole-3-thiol compounds - Google Patents
4-(0-halophenyl)-1,2,4-triazole-3-thiol compoundsInfo
- Publication number
- CA1048509A CA1048509A CA78301999A CA301999A CA1048509A CA 1048509 A CA1048509 A CA 1048509A CA 78301999 A CA78301999 A CA 78301999A CA 301999 A CA301999 A CA 301999A CA 1048509 A CA1048509 A CA 1048509A
- Authority
- CA
- Canada
- Prior art keywords
- triazole
- thiol
- chloro
- methyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
4-(o-Halophenyl)-1,2,4-Triazole-3-Thiol Compounds Abstract of the Disclosure A novel 4-(o-halophenyl)-1,2,4-triazole-3-thiol compound is described for use in the preparation of s-triazolo-[3,4-b]benzothiazole compounds. The s-triazolo [3,4-b] benzothiazole compounds are useful for the control of plant pathogens.
Description
~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 ' ~)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.
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 ' ~)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 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.
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 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 -.. . .
`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 _~_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.
.
.
-~)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
`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 _~_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.
.
.
-~)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
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-' :
.. , ~ . . . .
-~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.
~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.
~. ~
.
.
.'.'` ~ .
;;, . .
: .
-.
.. ~ 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-' :
.. , ~ . . . .
-~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.
~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.
~. ~
.
.
.'.'` ~ .
;;, . .
: .
-.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A 4-(o-halophenyl)-1,2,4-triazole-3-thiol com-pound of the formula (III) wherein R is hydrogen, C1-C11 alkyl, cyclopropyl or trifluoro-methyl;
R1 is hydrogen, bromo, chloro or fluoro;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, bromo, chloro, fluoro or tri-fluoromethyl with the limitation that at least one of R2 and R3 is hydrogen;
X is bromo, chloro or fluoro;
subject to the further limitation that when R1 is halogen, R is other than hydrogen and R2 is hydrogen.
R1 is hydrogen, bromo, chloro or fluoro;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, bromo, chloro, fluoro or tri-fluoromethyl with the limitation that at least one of R2 and R3 is hydrogen;
X is bromo, chloro or fluoro;
subject to the further limitation that when R1 is halogen, R is other than hydrogen and R2 is hydrogen.
2. me compound according to claim 1, namely 4-(2-chlorophenyl)-1,2,4-triazole-3-thiol.
3. The compound according to claim 1, namely 4-(2-chlorophenyl)-5-methyl-1,2,4-triazole-3-thiol.
4. The compound according to claim 1, namely 4-(2,4-dichlorophenyl)-5-methyl-1,2,4-triazole-3-thiol.
5. The compound according to claim 1, namely 4-(2,6-dichlorophenyl)-5-methyl-1,2,4-triazole-3-thiol.
6. The compound according to claim 1, namely 4-(2-chloro-5-methylphenyl)-5-methyl-1,2,4-triazole-3-thiol.
7. The compound according to claim 1, namely 4-(2-chloro-5-trifluoromethylphenyl)-5-methyl-1,2,4-triazole-3-thiol.
8. A process for preparing a 4-(o-halophenyl)-1,2,4-triazole-3-thiol compound of the formula (III) wherein R is hydrogen, C1-C11 alkyl, cyclopropyl or tri-fluoromethyl;
R1 is hydrogen, bromo, chloro or fluoro;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, bromo, chloro, fluoro or tri-fluoromethyl with the limitation that at least one of R2 and R3 is hydrogen;
X is bromo, chloro or fluoro;
subject to the further limitation that when R1 is halogen, R is other than hydrogen and R2 is hydrogen which comprises subjecting to cyclodehydration a 1-acyl-4-(o-halophenyl)-3-thiosemicarbazide compound of the formula (II)
R1 is hydrogen, bromo, chloro or fluoro;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, bromo, chloro, fluoro or tri-fluoromethyl with the limitation that at least one of R2 and R3 is hydrogen;
X is bromo, chloro or fluoro;
subject to the further limitation that when R1 is halogen, R is other than hydrogen and R2 is hydrogen which comprises subjecting to cyclodehydration a 1-acyl-4-(o-halophenyl)-3-thiosemicarbazide compound of the formula (II)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/449,141 US3937713A (en) | 1974-03-07 | 1974-03-07 | Process for the preparation of s-triazolo[3,4-b]benzothiazoles |
| CA75221381A CA1048506A (en) | 1974-03-07 | 1975-03-06 | Process for the preparation of s-triazolo (3,4-b) benzothiazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048509A true CA1048509A (en) | 1979-02-13 |
Family
ID=25667852
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA78301999A Expired CA1048509A (en) | 1974-03-07 | 1978-04-26 | 4-(0-halophenyl)-1,2,4-triazole-3-thiol compounds |
| CA78301998A Expired CA1048539A (en) | 1974-03-07 | 1978-04-26 | 1-acyl-4-(0-halophenyl) thiosemicarbazide compounds |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA78301998A Expired CA1048539A (en) | 1974-03-07 | 1978-04-26 | 1-acyl-4-(0-halophenyl) thiosemicarbazide compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1048509A (en) |
-
1978
- 1978-04-26 CA CA78301999A patent/CA1048509A/en not_active Expired
- 1978-04-26 CA CA78301998A patent/CA1048539A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1048539A (en) | 1979-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1195325A (en) | Imidazole derivatives, processes for the manufacture thereof and pharmaceutical preparations containing them | |
| CA1048506A (en) | Process for the preparation of s-triazolo (3,4-b) benzothiazoles | |
| Sasaki et al. | Ring Transformation of 1, 3, 4-Oxadiazole to s-Triazole-Fused Heterocycles. New Synthetic Route for Thiazolo [2, 3-c]-s-triazole and 7H-s-Triazolo [3, 4-b][1, 3, 4] thiadiazine | |
| US4082762A (en) | 4-(2-halophenyl)-1,2,4-triazole-3-thiol compounds | |
| L'Abbé et al. | Dimroth rearrangement of 5‐hydrazino‐1, 2, 3‐thiadiazoles | |
| CA1048509A (en) | 4-(0-halophenyl)-1,2,4-triazole-3-thiol compounds | |
| CN112390725B (en) | Preparation method of amide compound | |
| Sarodnick et al. | Quinoxalines. Part 12: Synthesis and structural study of 1-(thiazol-2-yl)-1H-pyrazolo [3, 4-b] quinoxalines—the dehydrogenative cyclization with hydroxylamine hydrochloride | |
| US4134914A (en) | 1-Acyl-4-substituted phenyl thiosemicarbazides | |
| CA1302420C (en) | Indene derivatives and methods | |
| Dawood et al. | A Convenient Access to Functionalized Pyrazole, Pyrazolyl‐Azole, and Pyrazolo [3, 4‐d] Pyridazine Derivatives | |
| EP3541798A1 (en) | 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-mercapto-1h-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile and processes of preparation | |
| Kojima et al. | Synthesis of indolizines and pyrrolo [2, 1‐b] azoles from 2‐pyridylmagnesium bromide and 2‐lithiated azoles using tris (alkylthio)‐cyclopropenyl cations as a three‐carbon building block | |
| KR790001654B1 (en) | Process for the preparation of s-triazolo(3,4-b)benzothiazoles | |
| KR790001653B1 (en) | Process for the preparation of s-triazolo(3,4-b)benzothiazoles | |
| US7238719B2 (en) | Process for producing 1,2,3-Triazole compounds | |
| KR790001652B1 (en) | Process for the preparation of s-triazolo(3,4-b)benzothiazoles | |
| NO157654B (en) | PROCEDURE FOR PREPARING 5,6,7,7A-TETRAHYDRO-4H-THIENO- (3,2-C) -PYRIDIN-ON DERIVATIVES. | |
| Talebizadeh et al. | A simple and efficient method for the synthesis of 4-tosyloxazoles from tosylmethyl isocyanide with α-ketoimidoyl chlorides | |
| Rozhkov et al. | Nucleophilic substitution in the series of (1, 2, 3-triazol-1-yl)-1, 2, 5-oxadiazoles. Reactions with N-, O-, and S-nucleophiles | |
| CA1116609A (en) | Process for preparing thiazole derivatives | |
| L'abbé et al. | Synthesis of 1‐Amino‐5‐(Substituted) Amino‐1, 2, 3‐Triazoles | |
| Britsun et al. | Reaction of 2-Aryl-5-R-5, 6-dihydro-7H-[1, 2, 4]-triazolo [5, 1-b][1, 3] thiazin-7-ones with Aryl Bromomethyl Ketones and Benzyl Bromide | |
| Mohareb et al. | Reaction of 4‐aryl‐3‐thiosemicarbazides with carbon disulfide: A facile synthesis of 2, 3‐dihydrothiazoles and their fused derivatives | |
| Ibrahim et al. | Month 2018 Synthesis and Chemical Reactivity of the Novel 4-Hydroxy-6-methyl-2, 5-dioxo-5, 6-dihydro-2H-pyrano [3, 2-c] quinoline-3-carboxaldehyde |