CN114478429B - 3-alkylthio isothiazole derivative and synthetic method thereof - Google Patents
3-alkylthio isothiazole derivative and synthetic method thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000004965 peroxy acids Chemical class 0.000 claims abstract description 11
- 238000001308 synthesis method Methods 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003570 air Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZJAFQAPHWPSKRZ-UHFFFAOYSA-N 4-nitrobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=C([N+]([O-])=O)C=C1 ZJAFQAPHWPSKRZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- -1 which is an aprotic Substances 0.000 description 2
- MFXSRTAQRKSLDX-UHFFFAOYSA-N 3-methylsulfanyl-5-phenyl-1,2-thiazole Chemical class S1N=C(SC)C=C1C1=CC=CC=C1 MFXSRTAQRKSLDX-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000003854 isothiazoles Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 3-alkylthio isothiazole derivative and a synthesis method thereof. alpha-thiocarbonyl-N, S-ketene is used as an initial raw material, peroxyacid is used as an accelerator, a 3-alkylthio isothiazole ring is constructed in one step, a series of 3-alkylthio isothiazole derivatives are generated, and the obtained 3-alkylthio isothiazole derivatives have certain potential pharmaceutical activity. The method only needs one-step reaction, and has the advantages of easily available raw materials, simple and convenient operation, mild synthesis reaction condition and high reaction efficiency.
Description
Technical Field
The invention relates to a 3-alkylthio isothiazole derivative and a synthesis method thereof, belonging to the technical field of chemical organic synthesis.
Background
The 3-alkylthio isothiazole derivative is a compound with wide biological activity, and can be used for central nervous system tranquilizer, medicine, herbicide, mothproofing agent, preservative, bactericide and the like. Therefore, the development of a novel method for synthesizing 3-alkylthio isothiazole derivatives is of great importance. At present, various methods are used for preparing 3-alkylthio isothiazole derivatives, but only 1 literature report on synthesizing 3-alkylthio isothiazole derivatives by using alpha-thiocarbonyl-N, S-ketene as a raw material is available. The related preparation method comprises the following steps: the alpha-thiocarbonyl-N, S-ketene reacts with iodine simple substance to form isothiazole five-membered ring iodized salt; then reacted with potassium iodide under heating (J.org.chem.2002, 67,5375). However, the above method needs to face complex synthesis steps, harsh conditions and low reaction yield, and needs a certain amount of iodine simple substance, so that the application of the method in the synthesis of the 3-alkylthio isothiazole derivative is limited to a certain extent.
In view of the complex steps, harsh conditions and low efficiency of the synthesis method for synthesizing 3-alkylthio isothiazole by adopting the alpha-thiocarbonyl-N, S-ketene as the raw material, the alpha-thiocarbonyl-N, S-ketene which is easy to prepare and has structural diversity and multiple reaction centers is used as the raw material, and only one-step oxidation cyclization reaction is needed, and R in the alpha-thiocarbonyl-N, S-ketene is regulated and controlled 1 、R 2 、R 2 And synthesizing a series of 3-alkylthio isothiazole derivatives with different structures by substituent groups.
Disclosure of Invention
The invention aims to realize the construction of an isothiazole ring by taking alpha-thiocarbonyl-N, S-ketene II which is easy to prepare, has structural diversity and multiple reaction centers as a raw material in one step, and synthesize the 3-alkylthio isothiazole derivative with potential pharmaceutical activity.
The invention provides a 3-alkylthio isothiazole derivative, which has the following molecular structural formula I:
R 1 selected from methyl, aryl, naphthalene, furan, thiophene or cyclopropane groups; r is R 2 Selected from methyl, ethyl, cyclopropane, or aryl; wherein the aryl is selected from phenyl and aryl with substituent groups on benzene ring, the substituent groups on benzene ring are selected from 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent groups is 1-5.
The invention provides a method for synthesizing a 3-alkylthio isothiazole derivative I, which takes alpha-thiocarbonyl-N, S-ketene II as a starting material and peroxy acid as an accelerator, and the 3-alkylthio isothiazole derivative I is produced by self-oxidation cyclization reaction in a solvent under the condition of heating or non-heating.
The molecular structural formula of the alpha-thiocarbonyl-N, S-ketene II is as follows:
R 1 selected from methyl, aryl, naphthalene, furan, thiophene or cyclopropane groups; r is R 2 Selected from methyl, ethyl, cyclopropane, or aryl; wherein the aryl is selected from phenyl and aryl with substituent groups on benzene ring, the substituent groups on the benzene ring are selected from 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent groups is 1-5; r is R 3 Selected from methyl, ethyl, benzyl, aryl, naphthalene ring, furan ring, thiophene ring, and cyclopropane group;
the synthetic route is shown in the following reaction formula:
wherein: the peroxyacid promoter is selected from peroxyacetic acid (CH) 3 CO 2 OH), peroxytrifluoroacetic acid (CF) 3 CO 2 OH), hydrogen peroxide (H) 2 O 2 ) Peroxybenzoic acid (PhCO) 2 OH), m-chloroperoxybenzoic acid (m-ClC 6 H 4 CO 2 OH), 4-nitroperoxybenzoic acid (p-NO 2 C 6 H 4 CO 2 OH), peroxyphenylacetic acid (PhCH) 2 CO 2 OH) and the molar ratio of the alpha-thiocarbonyl-N, S-ketene II to the peroxy acid is 1:2.0-1:5.0;
the reaction solvent is selected from one or more than two of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzotrifluoride, acetonitrile, toluene (PhMe), 1, 4-dioxane and Tetrahydrofuran (THF); the molar concentration of the alpha-thiocarbonyl-N, S-ketene II in the reaction solvent is 0.05-1.0M;
the reaction atmosphere is one or more than two of air, oxygen, nitrogen or argon; the reaction time is 0.1-48 hours; the reaction temperature is 0-130 ℃.
Further, in the above-mentioned technical scheme, the peroxy acid in the reaction for producing I from alpha-thiocarbonyl-N, S-ketene II is preferably m-ClC 6 H 4 CO 2 OH。
Further, in the above-mentioned technical scheme, the reaction of producing I from alpha-thiocarbonyl-N, S-ketene II is preferably carried out in toluene, which is an aprotic, nonpolar solvent.
Further, in the above-mentioned technical scheme, the reaction of producing I from alpha-thiocarbonyl-N, S-ketene II is preferably carried out under a nitrogen atmosphere.
Further, in the above technical scheme, the optimal reaction time for the reaction of alpha-thiocarbonyl-N, S-ketene II to form I is 1-3 hours.
Further, in the above technical scheme, the optimal reaction temperature for the reaction of alpha-thiocarbonyl-N, S-ketene II to form I is 50-90 ℃.
Further, in the above technical scheme, in the reaction of producing I from alpha-thiocarbonyl-N, S-ketene II, the preferred molar ratio of alpha-thiocarbonyl-N, S-ketene II to peroxy acid is 1:2.0.
The invention takes the alpha-thiocarbonyl-N, S-ketene II which is easy to prepare, has structural diversity and multiple reaction centers as an initial raw material, takes peroxy acid as an accelerator, and builds a 3-alkylthio isothiazole ring through an oxidative cyclization reaction to generate a series of 3-alkylthio isothiazole derivatives, and the obtained 3-alkylthio isothiazole derivatives have certain potential pharmaceutical activity. Compared with the reported method for synthesizing the isothiazole derivative by taking the alpha-thiocarbonyl-N, S-ketene as the raw material, the method only needs one-step reaction, has simple and convenient operation, mild condition, high synthesis reaction efficiency and high yield of 50-88 percent, and the product has good stereoselectivity and functional group diversity. The 3-alkylthio isothiazole skeleton structure synthesized by the invention can be used as an intermediate of the structures of medicines and various chemical products.
The invention has the following advantages:
1) The synthon alpha-thiocarbonyl-N, S-ketene II has structural diversity and can be used for synthesizing 3-alkylthio isothiazole derivatives I with different types and structures.
2) Synthon II is commercially available, low in cost and easy for industrial production.
3) Synthesis of 3-alkylthio isothiazole derivatives I using relatively nontoxic RCO at low cost 2 OH is used as an accelerator.
4) The 3-alkylthio isothiazole derivative I has high product yield up to 88% and only needs one step of isothiazole ring construction.
5) The synthesis reaction condition of the 3-alkylthio isothiazole derivative I is mild, and the temperature is 50-90 ℃.
6) The 3-alkylthio isothiazole derivative I has good stereoselectivity, multiple functional groups and wide application.
In a word, the invention utilizes the structural diversity and multiple reaction centers of the alpha-thiocarbonyl-N, S-ketene II to efficiently synthesize the 3-alkylthio isothiazole derivatives I with different types and structures, the raw materials are cheap and easy to obtain, only one-step reaction is needed to obtain a series of 3-alkylthio isothiazole derivative structures, the operation is simple and convenient, the condition is mild, and the yield of target products is high.
Detailed Description
The alpha-carbonyl-N, S-ketene A reacts with Lawson reagent B in toluene solvent at 110 ℃ to produce alpha-thiocarbonyl-N, S-ketene II. R in A 1 、R 2 、R 3 Wherein the definition is as in formula II.
The specific process is as follows: the alpha-carbonyl-N, S-ketene A (2.0 mmol) and the Lawson reagent B (1.0 mmol) are dissolved in 3mL of toluene, and the reaction is stirred in an oil bath at 110 ℃ for 1min, and the reaction is stopped when the reaction of the raw material alpha-carbonyl-N, S-ketene A is detected by TLC. After cooling to room temperature, volatile components were removed under reduced pressure, and then separated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v=50:1) to give the desired product ii. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
The following examples of starting materials 2a, 2b were prepared by the following literature methods:
Z.Q.Liu,P.Wu,Y.He,T.Yang,Z.K.Yu,Adv.Synth.Catal.2018,360,4381-4392.
the present invention will be further understood by the following examples, but the content of the present invention is not limited thereto.
Example 1
In a glove box, 1-methylsulfanyl-1-benzylamine-1-butene-3-phenyl-3-thioketone 2a (0.3 mmol) and m-chloroperoxybenzoic acid (0.60 mmol) were weighed in sequence into a 25mL Schlenk reaction flask, 2mL toluene was added under nitrogen, and the mixture was put into an oil bath at 60 ℃ to react for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature, volatile components were removed under reduced pressure, and then separated by silica gel column chromatography (petroleum ether (60-90 ℃) in ethyl acetate, v/v=20:1 as eluent) to give the desired product 1a (50 mg, yield 80%) as a yellow liquid. The target product was confirmed by nuclear magnetic resonance spectroscopy.
Data on characterization of the Compounds
3-methylsulfanyl-5-phenylisothiazole derivative (1 a), yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ7.55(dd,J＝7.7,2H,1.8Hz),7.42(m,3H),7.15(s,1H),2.69(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ167.57,163.97,130.66,129.80,129.28,126.63,118.17,14.17.
Example 2
In a glove box, 1-methylthio-1-benzylamine-1-butene-3-m-bromophenyl-3-thione 2b (0.3 mmol) and m-chloroperoxybenzoic acid (0.60 mmol) were weighed in sequence in a 25mL Schlenk reaction flask, toluene 2mL was added under nitrogen, and the mixture was put into an oil bath at 60℃to react for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature, volatile components were removed under reduced pressure, and then separated by silica gel column chromatography (petroleum ether (60-90 ℃) in ethyl acetate, v/v=20:1 as eluent) to give the objective product 1b (65 mg, yield 75%) as a yellow liquid. The target product was confirmed by nuclear magnetic resonance spectroscopy.
Data on characterization of the Compounds
3-methylsulfanyl-5-m-bromophenyl isothiazole derivative (1 b), yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ7.69(t,J＝1.8Hz,1H),7.52(m,1H),7.46(m,1H),7.29(m,1H),7.13(s,1H),2.68(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )165.76,164.31,132.69,132.62,130.82,129.54,125.33,123.36,118.85,14.22.
Example 3
The reaction procedure and operation are as in example 1, except that the m-ClC of 2a and 2a are as described in example 1 6 H 4 CO 2 The OH molar ratio was 1:1.5. The reaction was stopped, and the desired product 1a (43 mg, yield 70%) was obtained by working up.
Example 4
The reaction procedure and operation were as in example 1, except that PhMe was changed to DMF. The reaction was stopped, and the desired product 1a (38 mg, yield 62%) was obtained by working up.
Example 5
The reaction procedure and operation were as in example 1, except that DMF was changed to DMSO. The reaction was stopped, and the desired product 1a (40 mg, yield 65%) was obtained by working up.
Example 6
The reaction procedure and operation were as in example 1, except for the m-ClC 6 H 4 CO 2 OH is changed into CH 3 CO 2 OH. The reaction was stopped, and the desired product 1a (33 mg, yield 53%) was obtained by working up.
Example 7
The reaction procedure and operation were as in example 1, except for the m-ClC 6 H 4 CO 2 OH to PhCO 2 OH. The reaction was stopped, and the desired product 1a (38 mg, yield 61%) was obtained by working up.
Example 8
The reaction procedure and operation were as in example 1, except that N 2 Change to O 2 . The reaction was stopped, and the desired product 1a (34 mg, yield 55%) was obtained by working up.
Example 9
The reaction procedure and operation were as in example 1, except that N 2 Instead of air. The reaction was stopped, and the desired product 1a (37 mg, yield 60%) was obtained by working up.
Example 10
The reaction procedure and operation were the same as in example 1, except that the temperature of 60℃was changed to 40 ℃. The reaction was stopped, and the desired product 1a (31 mg, yield 51%) was obtained by working up.
The method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high reaction efficiency and diversity of functional groups, and only needs one-step reaction.
Claims (5)
1. A method for synthesizing a 3-alkylthio isothiazole derivative is characterized in that: taking alpha-thiocarbonyl-N, S-ketene II as a starting material and peroxy acid as an accelerator to carry out cyclization reaction to generate the 3-alkylthio isothiazole derivative I in one step;
the molecular structural formula of the alpha-thiocarbonyl-N, S-ketene II is as follows:
R 1 selected from methyl, aryl, naphthalene, furan, thiophene or cyclopropane groups;
R 2 selected from methyl, ethyl, cyclopropane, or aryl;
wherein the aryl is selected from phenyl and aryl with substituent groups on benzene ring, the substituent groups on the benzene ring are selected from 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent groups is 1-5;
R 3 selected from benzyl;
the synthetic route is shown in the following reaction formula:
the peroxyacid is one or more selected from peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid and peroxyphenylacetic acid.
2. The synthesis method according to claim 1, wherein:
the molar ratio of the alpha-thiocarbonyl-N, S-ketene II to the peroxyacid is 1:2.0-1:5.0;
the reaction solvent is selected from one or more than two of N, N-dimethylformamide, dimethyl sulfoxide, benzotrifluoride, acetonitrile, toluene, 1, 4-dioxane and tetrahydrofuran, and the molar concentration of alpha-thiocarbonyl-N, S-ketene II in the reaction solvent is 0.05-1.0M;
the reaction atmosphere is one or more than two of air, oxygen, nitrogen and argon; the reaction time is 0.1-48 hours; the reaction temperature is 0-130 ℃.
3. The synthesis method according to claim 2, characterized in that: the reaction time is 1-3 hours.
4. The synthesis method according to claim 2, characterized in that: the reaction temperature is 50-90 ℃.
5. The synthesis method according to claim 2, characterized in that: the molar ratio of the alpha-thiocarbonyl-N, S-ketene II to the peroxy acid is 1:2.0.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07304758A (en) * | 1994-05-13 | 1995-11-21 | Mitsui Toatsu Chem Inc | Production of 3-alkyl-5-aminoisothiazole mineral acid salts |
| CN108218804A (en) * | 2016-12-09 | 2018-06-29 | 中国科学院大连化学物理研究所 | A kind of 4- alkylthio groups -3- isoxazolidinones derivative and its synthetic method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07304758A (en) * | 1994-05-13 | 1995-11-21 | Mitsui Toatsu Chem Inc | Production of 3-alkyl-5-aminoisothiazole mineral acid salts |
| CN108218804A (en) * | 2016-12-09 | 2018-06-29 | 中国科学院大连化学物理研究所 | A kind of 4- alkylthio groups -3- isoxazolidinones derivative and its synthetic method |
Non-Patent Citations (5)
| Title |
|---|
| "Isothiazoles. III. Synthesis of isothiazolo[5,4-d]pyrimidines";Anderson, Richard C.等;Journal of Heterocyclic Chemistry;第12卷(第5期);883-887 * |
| "Novel Synthesis of cis-Nickel(II) 3-Alkylimino-3-alkyl(oraryl)thio-1-arylpropenethiolates and Their Application to the Preparation of 5-Aryl-3-(arylthio)isothiazoles";Dong Joon Lee等;J. Org. Chem.;第67卷;第5375 -5377页 * |
| Dong Joon Lee等."Novel Synthesis of cis-Nickel(II) 3-Alkylimino-3-alkyl(oraryl)thio-1-arylpropenethiolates and Their Application to the Preparation of 5-Aryl-3-(arylthio)isothiazoles".J. Org. Chem..2002,第67卷第5375 -5377页. * |
| Product class 15: isothiazoles;Brown, D. W.等;Science of Synthesis;第11卷;507-572 * |
| Synthesis of 2-Alkoxycarbonyl Enamino Thioaldehydes and Selenaldehydes (as Pentacarbonyltungsten(0) Complexes). Improved Synthesis of Simple and 2-Cyano Enamino Thioaldehydes and some Chemical Reactions of these Compounds;Motomu Muraoka等;J. CHEM. SOC. PERKTN TRANS. I;1241-1252 * |
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