CN111217767A - Method for preparing functionalized thiazole heterocyclic compound through Cu (I) -catalyzed multi-component cyclization reaction and application - Google Patents
Method for preparing functionalized thiazole heterocyclic compound through Cu (I) -catalyzed multi-component cyclization reaction and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
Abstract
The invention discloses a method for preparing a functionalized thiazole heterocyclic compound through Cu (I) -catalyzed multi-component cyclization reaction and application thereof, belonging to the field of chemical synthesis. According to the method, Cu (I) is used for catalysis, protonic acid such as pivalic acid is used as an additive, thioamide, aryl alkyne aldehyde and alcohol can generate a series of domino cyclization reactions under the reaction condition of 55-65 ℃, and the diversified functionalized thiazole heterocyclic compounds are obtained. The preparation method disclosed by the invention is simple to operate, the used catalytic system is simple and efficient, the method is environment-friendly, the substrates of thioamide, aryl alkynal and alcohol are wide in application range, the regioselectivity is good, a plurality of functional thiazole heterocyclic compounds can be efficiently synthesized, and the method has a wide application prospect in the aspects of development of bioactive molecules and medicines.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing a functionalized thiazole heterocyclic compound through Cu (I) -catalyzed multi-component cyclization reaction and application thereof.
Background
Active molecules containing thiazole structural units such as TAK-715, Ro 61-8048, NCH-31 and abafungin have powerful physiological active functions including anticancer, antiviral, antifungal, antitumor and the like in recent decades, the synthesis of thiazole compounds has received a great deal of attention, the coupling reaction of parent thiazole molecules catalyzed by transition metals is an important method for synthesizing functionalized thiazole compounds, however, thiazole parent compounds must be halogenated or metal pre-functionalized before cross-coupling, and the construction of parent thiazole molecules has been a problem for chemists.
CN102219757B discloses thiazole heterocyclic compounds and preparation and application thereof. The thiazole compound is (5-methyl- [1,3,4] thiadiazole-2-sulfydryl) -acetic acid (4-N, N dimethylamine-benzylidene) -hydrazide, and the thiazole compound can be used as a copper seawater corrosion inhibitor. The preparation method comprises the steps of mixing acetic acid and methanol to obtain methyl acetate, adding hydrazine hydrate to obtain acethydrazide, sequentially adding carbon disulfide and concentrated sulfuric acid to react respectively to obtain 2-mercapto-5-methyl- [1,3,4] thiadiazole, and then reacting with ethyl chloroacetate, hydrazine hydrate and p-N, N-dimethylbenzaldehyde respectively to obtain the target product. The preparation method has the advantages of more required raw material components, complex steps and longer preparation time of the product.
CN103450111B discloses a green synthesis method of a benzothiazole heterocyclic compound. The catalyst used in the reaction is water-soluble inorganic base, air is used as an oxidant, and the reactant alcohol and the o-amino thiophenol compound are subjected to direct oxidative condensation cyclization reaction in the air to synthesize the benzothiazole heterocyclic compound. The reaction temperature is 60-160 ℃, and the reaction time is 1-48 hours. The yield was 71-98%. Although the preparation process is simple, the reaction temperature is higher, the reaction time is longer, and the yield difference of the target product is larger.
Transition metal catalyzed multicomponent reactions (MCRs) have become a powerful tool in modern organic synthesis, allowing the rapid construction of a variety of complex molecules by forming new bonds in one step from readily available starting materials. The preparation of functionalized thiazole compounds by transition metal catalyzed three-component reaction has not been reported in the literature.
Therefore, we have developed a process for the preparation of functionalized thiazole heterocycles by Cu (I) -catalyzed multicomponent cyclization, in particular with CuBr (PPh)3)3The catalyst is composed of protonic acid such as pivalic acid and the like as additives, and the thioamide, the aryl alkynal and the alcohol can generate multicomponent cyclization reaction under the reaction condition of 60 ℃ to obtain the diversified and functionalized thiazole heterocyclic compound and research the application of the thiazole heterocyclic compound in preparing the insecticide.
Disclosure of Invention
In view of the deficiencies noted in the background above, it is an object of the present invention to provide a transition metal catalyzed multicomponent cyclization reaction to a functionalized thiazole heterocycle compound which allows the C-S, C-N and C-O bonds to be constructed in a single reaction step.
The invention also aims to provide a rapid and convenient synthesis method with mild conditions, wherein thiazole molecules are prepared from thioamide, so that the defects of harsh conditions, narrow substrate application range, multi-step synthesis and the like existing in the preparation of the thiazole molecules from thioamide in the prior art are overcome. Meanwhile, the application of the thiazole heterocyclic compound is disclosed, namely the application of the thiazole heterocyclic compound in preparing pesticides.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a method for preparing a functionalized thiazole heterocyclic compound through a Cu (I) -catalyzed multicomponent cyclization reaction, which comprises the steps of mixing thioamide shown in a formula 1 and alkynal shown in a formula 2, adding alcohol shown in a formula 3, a catalyst and protonic acid at room temperature, and stirring to obtain a target product shown in a formula 4, wherein the reaction formula is as follows:
wherein, the group R, R1、R2Is aryl or alkyl;
further, the amount of the thioamide substance represented by the formula 1 is 0.1 to 0.5mmol, and preferably, the amount of the thioamide substance is 0.3 mmol.
Further, the molar ratio of the thioamide shown in the formula 1 to the alkyne aldehyde shown in the formula 2 is 1:1-3, and preferably, the molar ratio of the thioamide to the alkyne aldehyde is 1: 1.5.
Further, the volume of the alcohol shown in the formula 3 is 2.5-3.5mL, and preferably, the volume of the alcohol is 3 mL; wherein the mass concentration of the alcohol is 0.033M; the alcohol includes, but is not limited to, one or more of methanol, ethanol, isopropanol, cyclohexanol, and benzyl alcohol.
Further, the catalyst includes, but is not limited to, CuBr (PPh)3)3、CuSO4·5H2O+PPh3、CuSO4·5H2O+PPh3、CuBr2、CuI、PdCl2、Pd(OAc)2、PdCl2(PPh3)2Preferably CuBr (PPh)3)3(ii) a The molar ratio of catalyst to thioamide of formula 1 is 0.05-3:1, preferably the molar ratio of catalyst to thioamide is 0.05: 1.
Further, the protonic acid includes, but is not limited to, pivalic acid, benzoic acid, p-toluenesulfonic acid, trifluoroacetic acid, preferably pivalic acid; the molar ratio of the protonic acid to the thioamide represented by formula 1 is 0.5-3:1, and preferably, the molar ratio of the protonic acid to the thioamide is 1:1.
Further, the temperature of the stirring is 55-65 ℃, preferably 60 ℃.
Further, the stirring time is 7 to 9 hours, preferably 8 hours.
Further, in the invention, thioamide shown in formula 1 and alkynal shown in formula 2 are mixed, alcohol shown in formula 3, catalyst and protonic acid are added at room temperature, then stirring is carried out, and silica gel chromatography separation is carried out after spin drying to obtain the target product shown in formula 4.
The invention also provides application of the thiazole heterocyclic compound in preparation of pesticides.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a method for preparing a functionalized thiazole heterocyclic compound by multi-component cyclization reaction catalyzed by transition metal, which prepares thiazole molecules by thioamide and overcomes the defects of harsh conditions, narrow substrate application range, multi-step synthesis and the like in the prior art for preparing the thiazole molecules by thioamide.
(2) The method for preparing the functionalized thiazole heterocyclic compound is simple and easy to operate, wide in application range of reaction substrates, good in regioselectivity, high in yield, economical in steps, capable of quickly synthesizing various types of functionalized thiazole heterocyclic compounds, and wide in application prospect in the preparation of natural products and medicines.
Detailed Description
For a better understanding of the present invention, the present invention is further described in conjunction with the following specific examples, wherein the terminology used in the examples is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. The raw materials used in the examples are all common commercial products, and therefore, the sources thereof need not be particularly limited.
Example 1
41.2mg (0.3mmol) of thioamide and 58.5mg (0.45mmol) of alkynal are introduced into a 10mL stirred flask, 3mL (0.033M) of methanol is added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh) is added3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 79% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
example 2
41.2mg (0.3mmol) of thioamide and 58.5mg (0.45mmol) of alkynal are introduced into a 10mL stirred flask, 3mL (0.033M) of ethanol are added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh) are added3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 77% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝9.8Hz,2H),7.59(s,1H),7.47-7.32(m,8H),5.63(s,1H),3.63-3.54(m,2H),1.29(t,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)：δ169.0,141.7,141.2,133.8,130.1,129.0,128.8,128.3,126.7,126.5,77.6,64.8,15.4.
HR-MALDI-MS：m/z calcd.for C18H17NOS[M+H]+:296.1104,found:296.1104.
example 3
41.2mg (0.3mmol) of thioamide, 58.5mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of isopropanol are added at room temperature, and 14.0mg (0.015mmol) of catalyst CuBr (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 74% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.9Hz,2H),7.55(s,1H),7.46-7.36(m,8H),5.74(s,1H),3.79-3.73(m,1H),1.24(dd,J＝14.6,6.1Hz,6H).
13C NMR(101MHz,CDCl3)：δ169.0,141.5,141.0,133.8,130.1,129.0,128.7,128.2,126.8,126.5,74.8,69.8,22.5,22.2.
HR-MALDI-MS：m/z calcd.for C19H19NOS[M+H]+:310.1260,found:310.1256.
example 4
41.2mg (0.3mmol) of thioamide, 58.5mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of cyclohexanol are added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 68% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.91-7.88(m,2H),7.54-7.52(m,1H),7.46-7.43(m,2H),7.41-7.35(m,5H),7.32(d,J＝7.2Hz,1H),5.79(s,1H),3.45(s,1H),1.91(s,2H),1.75(d,J＝5.1Hz,2H),1.53–1.40(m,3H),1.28–1.22(m,3H).
13C NMR(101MHz,CDCl3)：δ168.9,142.7,141.7,140.9,133.8,130.1,129.0,128.7,128.2,126.9,126.5,75.5,74.4,32.5,32.2,25.9,24.1.
HR-MALDI-MS：m/z calcd.for C22H23NOS[M+H]+:350.1573,found:350.1572.
example 5
41.2mg (0.3mmol) of thioamide, 58.5mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of benzyl alcohol are added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 65% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.92-7.88(m,2H),7.57(s,1H),7.47(d,J＝7.1Hz,2H),7.42-7.31(m,11H),5.69(s,1H),4.63-4.56(m,2H).
13C NMR(101MHz,CDCl3)：δ169.2,141.4,141.2,140.5,137.6,133.6,130.1,129.0,128.8,128.6,128.4,127.9,127.8,126.9,126.4,76.4,70.5.
HR-MALDI-MS：m/z calcd.for C23H19NOS[M+H]+:358.1260,found:358.1258.
example 6
41.2mg (0.3mmol) of thioamide, 71.1mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of methanol are added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 74% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.90-7.87(m,2H),7.59(d,J＝0.8Hz,1H),7.40(dd,J＝5.0,1.9Hz,3H),7.18(s,1H),7.14(d,J＝1.2Hz,2H),5.43(s,1H),3.39(s,3H),2.26(d,J＝3.3Hz,6H).
13C NMR(101MHz,CDCl3)：δ169.1,141.6,141.0,137.9,137.2,137.0,133.6,130.2,130.0,129.1,128.0,126.5,124.3,79.5,57.0,20.0,19.7.
HR-MALDI-MS：m/z calcd.for C19H19NOS[M+H]+:310.1260,found:310.1255.
example 7
41.2mg (0.3mmol) of thioamide, 73.8mg (0.45mmol) of alkynal substrate were placed in a 10mL stirred flask, 3mL (0.033M) of methanol was added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 76% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.92-7.87(m,2H),7.69-7.64(m,2H),7.43-7.34(m,5H),7.29-7.25(m,1H),5.94(s,1H),3.44(s,3H).
13C NMR(101MHz,CDCl3)：δ169.1,141.8,139.2,138.3,133.7,132.9,130.2,129.8,129.5,129.0,127.6,127.5,126.5,75.7,57.3.
HR-MALDI-MS：m/z calcd.for C17H14ClNOS[M+H]+:316.0557,found:316.0557.
example 8
41.2mg (0.3mmol) of thioamide and 93.2mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of methanol is added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 74% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.91-7.87(m,2H),7.60(s,1H),7.53(s,1H),7.51(s,1H),7.43-7.40(m,3H),7.31(d,J＝8.7Hz,2H),5.47(s,1H),3.41(s,3H).
13C NMR(101MHz,CDCl3)：δ169.5,141.6,140.5,139.7,133.6,132.0,130.3,129.1,128.5,126.5,122.4,78.8,57.1.
HR-MALDI-MS：m/z calcd.for C17H14BrNOS[M+H]+:360.0052,found:360.0049.
example 9
51.3mg (0.3mmol) of thioamide, 71.1mg (0.45mmol) of alkynal substrate are placed in a 10mL stirred flask, 3mL (0.033M) of methanol are added at room temperature, and 14.0mg (0.015mmol) of CuBr catalyst (PPh)3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in 76% yield.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.81(d,J＝8.7Hz,2H),7.57(d,J＝0.7Hz,1H),7.44-7.35(m,7H),5.49(s,1H),3.41(s,3H).
13C NMR(101MHz,CDCl3)：δ167.7,141.6,141.5,140.5,136.1,132.2,129.3,128.9,128.5,127.7,126.8,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H14ClNOS[M+H]+:316.0557,found:316.0554.
example 10
56.4mg (0.3mmol) of thioamide, 71.1mg (0.45mmol) of alkynal substrate are introduced into a 10mL stirred reaction flask, 3mL (0.033M) of methanol are added at room temperature, and14.0mg (0.015mmol) of catalyst CuBr (PPh) was added3)3And 30.6mg (0.3mmol) of pivalic acid, stirred at 60 ℃ for 8 hours, spin-dried and then separated by silica gel chromatography to give the desired product in a yield of 72%.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ8.75(d,J＝8.1Hz,1H),7.92-7.87(m,2H),7.78-7.75(m,1H),7.72(d,J＝0.7Hz,1H),7.56-7.51(m,2H),7.50-7.46(m,3H),7.44-7.40(m,2H),7.36(d,J＝7.2Hz,1H),5.57(s,1H),3.45(s,3H).
13C NMR(101MHz,CDCl3)：δ168.4,141.8,141.0,140.4,134.0,128.8,128.6,128.5,128.4,127.3,126.8,126.4,125.8,125.0,79.6,57.1.
HR-MALDI-MS：m/z calcd.for C21H17NOS[M+H]+:332.1104,found:332.1104.
example 11
The difference from example 1 is that the amount of thioamide substance is 0.1mmol, the molar ratio of thioamide to alkynal is 1:1, the molar ratio of pivalic acid to thioamide is 0.5:1, stirring is carried out at 55 ℃ for 7 hours, after drying by spin-drying, the desired product is isolated by silica gel chromatography. The yield was 74%.
The remaining raw material contents and the preparation method were the same as in example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
example 12
The difference from example 1 is that the amount of thioamide substance is 0.5mmol, the molar ratio of thioamide to alkynal is 1:3, the molar ratio of pivalic acid to thioamide is 3:1, stirring is carried out at 65 ℃ for 9 hours, spin-drying and then chromatographic separation is carried out on silica gel to obtain the desired product. The yield was 68%.
The remaining raw material contents and the preparation method were the same as in example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 1
The difference from example 1 is that the amount of thioamide substance is 0.05mmol and the molar ratio of thioamide to alkynal is 1: 0.5. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 68%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 2
The difference from example 1 is that the amount of thioamide substance is 0.55mmol and the molar ratio of thioamide to alkynal is 1: 3.5. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 70%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 3
The difference from example 1 is the catalyst CuBr (PPh)3)3The molar ratio to thioamide was 0.02: 1. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 72%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 4
The difference from example 1 is the catalyst CuBr (PPh)3)3The molar ratio to thioamide was 3.5: 1. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 60%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 5
The difference from example 1 is that the molar ratio of pivalic acid to thioamide is 0.3: 1. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 72%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 6
The difference from example 1 is that the molar ratio of pivalic acid to thioamide was 3.5: 1. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 69%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 7
The difference from example 1 is that the catalyst CuBr (PPh) is added3)3And pivalic acid, stirred at 50 ℃ for 10 h. After spin-drying, the target product was isolated by silica gel chromatography with a yield of 72%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
comparative example 8
The difference from example 1 is that the catalyst CuBr (PPh) is added3)3And pivalic acid, stirred at 70 ℃ for 6 h. Separating with silica gel after spin dryingTo the target product, yield was 74%.
Other sources and contents of raw materials and preparation method are the same as those of example 1.
Process for preparing thiazole heterocyclic compounds1H NMR，13C NMR and HR-ESI-MS spectrum data are respectively as follows:
1H NMR(400MHz,CDCl3)：δ7.89(d,J＝3.5Hz,2H),7.59(s,1H),7.45-7.37(m,8H),5.51(s,1H),3.42(s,3H).
13C NMR(101MHz,CDCl3)：δ169.3,150.0,141.2,140.5,133.5,133.1,131.6,130.3,129.3,129.2,129.1,128.9,128.5,127.2,127.1,126.8,126.5,79.5,57.1.
HR-MALDI-MS：m/z calcd.for C17H15NOS[M+H]+:282.0947,found:282.0944.
in summary, when methanol and alkynal are used as one of the raw materials (example 1), the yield of the objective product is 79%, when methanol is replaced by ethanol, isopropanol, cyclohexanol or benzyl alcohol, the yield of the objective product is reduced, but the yields are all above 65%, when alkynal of different structures are used in the examples, the yields are varied, but the yields are all above 74%, the raw material ranges or the reaction temperature or the stirring time of the comparative examples 1 to 8 are outside the claimed range, and it can be seen that the yields obtained after performing flash column chromatography on the objective product are all lower than those of the corresponding examples, and the yield of the objective product is as high as 79%. Therefore, the thiazole heterocyclic compound prepared by the method of the invention has high yield.
Performance testing
Insecticidal activity tests were conducted on the insecticides prepared from the thiazole heterocyclic compounds prepared in examples 1 to 12, respectively, using aphids as test subjects, and selecting an area of 10m2Repeating for 3 times, taking an average value, designing a random block group, and setting isolation rows among cells, wherein the specific operation process is as follows: the products prepared in each example were weighed, and N, N-dimethylformamide was added to prepare 15g/L of a mother liquor, which was diluted to a concentration of 600ppm with an aqueous solution containing 0.3mL/L of Triton X-100 at the time of the experiment. Spraying prepared concentration after the wingless adult aphids stably feed on the bean sproutsThe aphid death number is counted after 24 hours, wherein the aphid death number is 600ppm of liquid medicine. The control group was an aqueous solution containing 0.3mL/L Triton X100. Mortality (%) calculation formula: mortality (%) - (number of control live insects-number of treated live insects)/number of control live insects × 100%. The results are shown in Table 1 below.
Table 1:
as shown in Table 1, the insecticidal activity of the liquid medicines prepared in examples 1-12 on aphids is high, the death rate of the aphids reaches 100%, the death rate of the aphids in a control group is 60%, and the thiazole heterocyclic compound prepared by the invention has a good insecticidal effect.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A method for preparing a functionalized thiazole heterocyclic compound through a Cu (I) -catalyzed multi-component cyclization reaction is characterized in that thioamide shown in a formula 1 and alkyne aldehyde shown in a formula 2 are mixed, alcohol shown in a formula 3, a catalyst and protonic acid are added at room temperature, and then stirring is carried out to obtain a target product shown in a formula 4, wherein the reaction formula is as follows:
wherein, the group R, R1、R2Is aryl or alkyl.
2. The method of claim 1, wherein: the amount of the thioamide substance represented by the formula 1 is 0.1 to 0.5 mmol.
3. The method of claim 1, wherein: the molar ratio of the thioamide shown in the formula 1 to the alkynal shown in the formula 2 is 1: 1-3.
4. The method of claim 1, wherein: the volume of the alcohol shown in the formula 3 is 2.5-3.5 mL.
5. The method of claim 1, wherein: the molar ratio of the catalyst to the thioamide represented by the formula 1 is 0.05-3: 1.
6. The method of claim 1, wherein: the molar ratio of the protonic acid to the thioamide represented by the formula 1 is 0.5-3: 1.
7. The method of claim 1, wherein: the stirring temperature is 55-65 ℃.
8. The method of claim 1, wherein: the stirring time is 7-9 hours.
9. The method of claim 1, wherein: mixing thioamide shown in a formula 1 and alkynal shown in a formula 2, adding alcohol shown in a formula 3, a catalyst and protonic acid at room temperature, stirring, carrying out spin drying, and carrying out silica gel chromatography separation to obtain a target product shown in a formula 4.
10. Use of a thiazole heterocyclic compound prepared by the process according to any of claims 1 to 9 for the preparation of a pesticide.
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| CN101778834A (en) * | 2007-06-28 | 2010-07-14 | 辛根塔有限公司 | New herbicides |
| CN104650060A (en) * | 2014-12-17 | 2015-05-27 | 南开大学 | Piperidine thiazole derivatives as well as preparation method and use of piperidinethiazole derivatives |
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| CN101778834A (en) * | 2007-06-28 | 2010-07-14 | 辛根塔有限公司 | New herbicides |
| CN104650060A (en) * | 2014-12-17 | 2015-05-27 | 南开大学 | Piperidine thiazole derivatives as well as preparation method and use of piperidinethiazole derivatives |
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| YAJUN WANG ET AL.: "Cu(I)-Catalyzed Three-Component Cyclization for the Construction of Functionalized Thiazoles", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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| EP4129292A1 (en) | 2021-08-04 | 2023-02-08 | OnychoPharm GmbH | Formulation for substituted 2-aminothiazoles in the treatment of fungal and fungal-bacterial infections of the nail |
| WO2023011750A1 (en) | 2021-08-04 | 2023-02-09 | Onychopharm Gmbh | Formulation for substituted 2-aminothiazoles in the treatment of fungal and fungal-bacterial infections of the nail |
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