CN112552257A - 3, 5-disubstituted isothiazole compound and synthesis method and application thereof - Google Patents
3, 5-disubstituted isothiazole compound and synthesis method and application thereof Download PDFInfo
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- CN112552257A CN112552257A CN202011472808.1A CN202011472808A CN112552257A CN 112552257 A CN112552257 A CN 112552257A CN 202011472808 A CN202011472808 A CN 202011472808A CN 112552257 A CN112552257 A CN 112552257A
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- phenylisothiazole
- compound
- isothiazole
- reaction
- disubstituted
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- -1 3, 5-disubstituted isothiazole compound Chemical class 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 3
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 26
- ZOPJHVMKJAHTFS-UHFFFAOYSA-N 3,5-diphenyl-1,2-thiazole Chemical compound C=1C(C=2C=CC=CC=2)=NSC=1C1=CC=CC=C1 ZOPJHVMKJAHTFS-UHFFFAOYSA-N 0.000 claims description 26
- 229940107816 ammonium iodide Drugs 0.000 claims description 26
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 25
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- CPTWSALCFNKHDA-UHFFFAOYSA-N ClC=1C=C(C=C(C=1)Cl)C1=CC(=NS1)C1=CC=CC=C1 Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=NS1)C1=CC=CC=C1 CPTWSALCFNKHDA-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 4
- QTRJTMPLVIRDHO-UHFFFAOYSA-N 3-phenyl-1,2-thiazole Chemical compound S1C=CC(C=2C=CC=CC=2)=N1 QTRJTMPLVIRDHO-UHFFFAOYSA-N 0.000 claims description 3
- QHGIJBYILYALFB-UHFFFAOYSA-N 5-methyl-3-phenyl-1,2-thiazole Chemical compound S1C(C)=CC(C=2C=CC=CC=2)=N1 QHGIJBYILYALFB-UHFFFAOYSA-N 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- PRTOMNREMUFGHR-UHFFFAOYSA-N C1=C(C=CC2=CC=CC=C12)C1=NSC(=C1)C1=CC2=CC=CC=C2C=C1 Chemical compound C1=C(C=CC2=CC=CC=C12)C1=NSC(=C1)C1=CC2=CC=CC=C2C=C1 PRTOMNREMUFGHR-UHFFFAOYSA-N 0.000 claims description 3
- BKSHDVHEBPDTLG-UHFFFAOYSA-N C1=CC=CC=2C3=CC=CC=C3N(C1=2)C1=CC=C(C=C1)C1=NSC(=C1)C1=CC=CC=C1 Chemical compound C1=CC=CC=2C3=CC=CC=C3N(C1=2)C1=CC=C(C=C1)C1=NSC(=C1)C1=CC=CC=C1 BKSHDVHEBPDTLG-UHFFFAOYSA-N 0.000 claims description 3
- CTSUNBVPJKMDJB-UHFFFAOYSA-N CC(C)(C)C1=CC(=NS1)C1=CC=CC=C1 Chemical compound CC(C)(C)C1=CC(=NS1)C1=CC=CC=C1 CTSUNBVPJKMDJB-UHFFFAOYSA-N 0.000 claims description 3
- BHXIZMUMPVZLPG-UHFFFAOYSA-N ClC=1C=C(C=CC=1)C1=CC(=NS1)C1=CC=CC=C1 Chemical compound ClC=1C=C(C=CC=1)C1=CC(=NS1)C1=CC=CC=C1 BHXIZMUMPVZLPG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- NYYCIWGXNDHGMS-UHFFFAOYSA-N S1C(=CC=C1)C1=NSC(=C1)C=1SC=CC=1 Chemical compound S1C(=CC=C1)C1=NSC(=C1)C=1SC=CC=1 NYYCIWGXNDHGMS-UHFFFAOYSA-N 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 3
- 229940077484 ammonium bromide Drugs 0.000 claims description 3
- 229960001040 ammonium chloride Drugs 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- GCJTZGLHWFXNSS-UHFFFAOYSA-N 5-phenyl-1,2-thiazole Chemical compound S1N=CC=C1C1=CC=CC=C1 GCJTZGLHWFXNSS-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 2
- ZOUQIAGHKFLHIA-UHFFFAOYSA-L copper;n,n-dimethylcarbamodithioate Chemical compound [Cu+2].CN(C)C([S-])=S.CN(C)C([S-])=S ZOUQIAGHKFLHIA-UHFFFAOYSA-L 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- ZWWQICJTBOCQLA-UHFFFAOYSA-N o-propan-2-yl (propan-2-yloxycarbothioyldisulfanyl)methanethioate Chemical compound CC(C)OC(=S)SSC(=S)OC(C)C ZWWQICJTBOCQLA-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 230000005693 optoelectronics Effects 0.000 claims 1
- 229910052979 sodium sulfide Inorganic materials 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 238000003756 stirring Methods 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 6
- 229910052723 transition metal Inorganic materials 0.000 abstract description 5
- 150000003624 transition metals Chemical class 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 30
- 238000001228 spectrum Methods 0.000 description 28
- 239000000047 product Substances 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 238000004896 high resolution mass spectrometry Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000004821 distillation Methods 0.000 description 15
- 238000010791 quenching Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 238000012512 characterization method Methods 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 230000000171 quenching effect Effects 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000010189 synthetic method Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- 150000007979 thiazole derivatives Chemical class 0.000 description 2
- YECVQOULKHBGEN-UHFFFAOYSA-N 1,3-diphenylprop-2-yn-1-one Chemical compound C=1C=CC=CC=1C(=O)C#CC1=CC=CC=C1 YECVQOULKHBGEN-UHFFFAOYSA-N 0.000 description 1
- NZJRLYZNRXZOMI-UHFFFAOYSA-N 1,3-dithiophen-2-ylprop-2-yn-1-one Chemical compound O=C(C#Cc1cccs1)c1cccs1 NZJRLYZNRXZOMI-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- UKFWSNCTAHXBQN-UHFFFAOYSA-N ammonium iodide Chemical compound [NH4+].[I-] UKFWSNCTAHXBQN-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- MZGNSEAPZQGJRB-UHFFFAOYSA-N dimethyldithiocarbamic acid Chemical compound CN(C)C(S)=S MZGNSEAPZQGJRB-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000003854 isothiazoles Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- HSNHLHNSJCYPNU-UHFFFAOYSA-N o-propan-2-yl propan-2-ylsulfanylmethanethioate Chemical compound CC(C)OC(=S)SC(C)C HSNHLHNSJCYPNU-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005936 thiocarbonylation reaction Methods 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
-
- 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
-
- 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
- C07D417/10—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 linked by a carbon chain containing aromatic rings
-
- 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
- C07D417/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and discloses a 3, 5-disubstituted isothiazole compound, a synthesis method and application thereof, wherein the structural formula of the compound is shown as a formula (II), wherein: r1、R2Each independently represents hydrogen, a heterocyclic group, a phenyl derivative or an alkane. The 3, 5-disubstituted isothiazole compounds are synthesized by taking the alkynone compounds as raw materials, heating and stirring the alkynone compounds under the condition of adding a solvent without transition metal catalysis and reacting the alkynone compounds by a one-pot method, and except for final products, the intermediates in the conversion process do not need to be dividedSeparation and purification, namely synthesis can be completed in one step, so that industrial production is easy to realize, and capital and labor input can be reduced for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 3, 5-disubstituted isothiazole compound, and a synthesis method and application thereof.
Background
Sulfur-containing heterocycles are very important structural frameworks in organic heterocycles, exist in a plurality of drug molecules with biological activity and natural products, and the derivatives of isothiazole play an important role in the unique heterocyclic structure and are widely applied to the fields of medicines and pesticides, chemical reagents, photoelectric materials, industry, dyes, polymer auxiliaries and the like. Although the synthesis technology of isothiazole has been developed quite rapidly in recent decades, most of the synthetic heterocyclic rings are harsh and require expensive transition metals or ligands which are difficult to prepare as catalysts, and these synthetic methods often require multi-step synthesis, have low chemical selectivity, low functional group compatibility, and generate a large amount of inorganic salts. Therefore, how to simply and efficiently synthesize the thiazole derivative has important scientific significance and research value.
In recent years, researchers have also made reports on the synthesis of thiazole derivatives, such as the following: (a) commun., 2017, 53, 11060; (b) CHEMISTRYLETTERS, pp.1691-1692, 1984; (c) tetrahedron Letters, Vo1.24, No.35, pp 3729-; (d) org.biomol.chem., 2007, 5, 1381-. However, in the synthesis method described in the above document, it is still necessary to add a certain amount of metal or noble metal (Pt, Cu or Ni) catalyst, which is disadvantageous for industrialization of the synthesis method. Therefore, it is still necessary to develop a synthetic method which is convenient for industrial production.
Disclosure of Invention
The invention aims to provide a synthesis method and application of a 3, 5-disubstituted isothiazole compound, wherein the synthesis method takes an alkynone compound as a raw material and can synthesize the 3, 5-disubstituted isothiazole compound without transition metal catalysis.
In order to achieve the purpose, the invention adopts the following technical scheme:
a3, 5-disubstituted isothiazole compound having the structural formula shown in formula (II):
Preferably, the substituent of the phenyl derivative is halogen, C1-10 alkyl, alkoxy, sulfenyl or carbazolyl, and the number of the substituent on the benzene ring is 1-5; the heterocyclic group is furan, thiophene, pyrrole or naphthalene ring.
Preferably, said R is1、R2May be the same or different.
Preferably, said R is1When the substituent is a single substituent, the single substituent is a halogenated group independently substituted at 3 and 4 positions on a benzene ring.
Preferably, said R is1When it is polysubstituent and the R2When the substituent is a single substituent, the polysubstituent can be a halogenated group which is disubstituted at the 3-position and the 5-position on a benzene ring; the monosubstituent can be a 2-position and a 3-position on a benzene ring respectively substituted halogenated group.
Preferably, the compound is any one of: 3, 5-diphenylisothiazole, 5- (3-chlorophenyl) -3-phenylisothiazole, 5- (3-fluorophenyl) -3-phenylisothiazole, 5- (3, 5-dichlorophenyl) -3-phenylisothiazole, 3, 5-di (naphthalen-2-yl) isothiazole, 3, 5-di (thien-2-yl) isothiazole, 5-phenyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) phenyl) isothiazole, 5-phenylisothiazole, and mixtures thereof, 3- (4, 4-dimethylthiopyran-7-yl) -5-phenylisothiazole, 3- (4- (9H-carbazol-9-yl) phenyl) -5-phenylisothiazole, 3-phenylisothiazole, 5-methyl-3-phenylisothiazole, 5- (tert-butyl) -3-phenylisothiazole.
A synthetic method of 3, 5-disubstituted isothiazole compounds comprises the following steps of mixing an alkynone compound with a general formula (I), a nitrogen source, a sulfur source and a solvent, and carrying out heating reaction to obtain the 3, 5-disubstituted isothiazole compounds with a general formula (II), wherein the synthetic route is as follows:
wherein: r1、R2Each independently represents hydrogen, a heterocyclic group, a phenyl derivative or an alkane.
The synthesis mechanism of the 3, 5-disubstituted isothiazole compound is as follows:
the reaction mechanism of the synthesis method is as follows: NH (NH)4Thermal decomposition of I can release NH3，NH3The nucleophilic addition reaction is preferentially carried out on the intermediate A and the alkynone (raw material 1) through the regioselective hydrogenation to generate an intermediate A, and the intermediate C is subjected to EtOCS2Nucleophilic attack of K on carbonyl and subsequent intramolecular cyclization reaction to obtain intermediate C to form an unstable quaternary heterocycle, and then instantaneously dissociating potassium O-ethylsulfate to form thiocarbonylation intermediate D. In a continuous intramolecular cyclization/I2The intermediate D is finally converted to the product 2 in an oxidation cascade, in which I2By NH4I is obtained by decomposition.
Preferably, the sulphur source is one of thioacetamide, copper dimethyldithiocarbamate, diisopropyl xanthate disulphide, potassium ethyl xanthate or sodium sulphide.
More preferably, the sulfur source is potassium ethyl xanthate.
Preferably, the nitrogen source is one of ammonium iodide, ammonium chloride, ammonium bromide, ammonium acetate or ammonia water.
More preferably, the nitrogen source is ammonium iodide. Ammonium iodide is both a source of "N" and NH4Thermal decomposition of I can release NH3，NH3The intermediate is generated by nucleophilic addition reaction preferentially with alkynone through regioselective hydrogenation, so that the next step can be smoothly reacted.
Preferably, the solvent is at least one of N, N-Dimethylformamide (DMF), N-methylpyrrolidone, dimethylacetamide, or dimethylsulfoxide.
More preferably, the solvent is N, N-dimethylformamide.
Preferably, the temperature of the heating reaction is 90 ℃ to 130 ℃.
Preferably, the heating reaction time is 8 to 12 hours.
Preferably, in the heating reaction, the molar ratio of the alkynone compound, the sulfur source and the nitrogen source is 1 (1.2-1.5) to (4-4.5).
More preferably, in the heating reaction, the molar ratio of the alkynone compound, the sulfur source and the nitrogen source is 1:1.2: 4.
The invention also provides application of the 3, 5-disubstituted isothiazole compound in preparation of medicines or photoelectric materials.
The invention has the advantages that:
the 3, 5-disubstituted isothiazole compound is synthesized by taking the alkynone compound as a raw material without transition metal catalysis, heating and stirring under the condition of adding a solvent and carrying out a one-pot reaction, and the synthesis is finished in one step without separating and purifying an intermediate in the conversion process except a final product, so that the industrialized production is easy to realize, and the fund and labor investment can be reduced for industrial production.
Detailed Description
For a further understanding of the invention, preferred embodiments of the invention are described below with reference to the examples to further illustrate the features and advantages of the invention, and any changes or modifications that do not depart from the gist of the invention will be understood by those skilled in the art to which the invention pertains, the scope of which is defined by the scope of the appended claims.
Those who do not specify specific conditions in the examples of the present invention follow conventional conditions or conditions recommended by the manufacturer. The raw materials, reagents and the like which are not indicated for manufacturers are all conventional products which can be obtained by commercial purchase.
Example 1
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), dimethyl dithiocarbamate (182mg, 0.6mmo1), ammonium iodide (290mg, 2mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (76mg) in a yield of 62.4% after completion of the reaction.
Example 2
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenylpropan-2-yn-1-one (103mg, 0.5mmo1), thioacetamide (75mg, 0.6mmo1) and ammonium iodide (290mg, 2mmo1) were added to a 25mL reaction tube, and the mixture was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to complete the reaction, whereby 3, 5-diphenylisothiazole (56mg) was obtained in a yield of 48%.
Example 3
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), diisopropyl xanthogen disulfide (162mg, 0.6mmo1), ammonium iodide (290mg, 2mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (85mg) in a yield of 72.5% after completion of the reaction.
Example 4
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (96mg, 0.6mmo1) and ammonium iodide (290mg, 2mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (105mg) in a yield of 89%.
Example 5
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium bromide (98mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the mixture was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to complete the reaction, whereby 3, 5-diphenylisothiazole (66mg) was obtained in a yield of 56.2%.
Example 6
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium acetate (77mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the mixture was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to complete the reaction, whereby 3, 5-diphenylisothiazole (98mg) was obtained in a yield of 83%.
Example 7
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium chloride (53.4mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 130 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (43mg) in a yield of 37%.
Example 8
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred at 130 ℃ for 12 hours under dimethylacetamide (2mL) conditions to obtain 3, 5-diphenylisothiazole (69mg) in 58.6% yield after completion of the reaction.
Example 9
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the mixture was stirred under N-methylpyrrolidone (2mL) at a reaction temperature of 130 ℃ for 12 hours to complete the reaction, whereby 3, 5-diphenylisothiazole (81mg) was obtained in a yield of 68.6%.
Example 10
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred at 130 ℃ in dimethyl sulfoxide (2mL) for 12 hours to obtain 3, 5-diphenylisothiazole (47mg) in 38.6% yield after completion of the reaction.
Example 11
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 90 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (80mg) in a yield of 67.6% after completion of the reaction.
Example 12
The synthetic route of the 3, 5-diphenylisothiazole of this example is:
the method comprises the following specific steps:
1, 3-Diphenyl-2-yn-1-one (103mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1) were added to a 25mL reaction tube, respectively, and the reaction was stirred under N, N-dimethylacetamide (2mL) at a reaction temperature of 110 ℃ for 12 hours to obtain 3, 5-diphenylisothiazole (92mg) in a yield of 78.3%.
After the reactions of examples 1 to 12 were completed, ethyl acetate was added to carry out quenching reaction, and then saturated brine was added to wash the reaction mixture, the organic phase was separated, the aqueous phase was extracted with ethyl acetate repeatedly for 3 times, the organic phase was combined, dried over anhydrous sodium sulfate was added, the solvent was removed by distillation under reduced pressure, and a white solid was obtained after separation by column chromatography. Isolated in example 4 to yield 105mg, isolated in 89% yield.
The products obtained in examples 1 to 12 were taken for qualitative detection by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometry (HRMS), and the detection data of the products were consistent (to avoid redundancy, only the test data of the product obtained in example 4) as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.03–7.98(m，2H)，7.76(s，1H)，7.69–7.63(m，2H)，7.51–7.41(m，6H).13C NMR(125MHz，CDCl3)δ168.2，168.2，134.8，130.9，129.6，129.2(2C)，128.8(2C)，126.8，126.6，117.5.HRMS(ESI)(m/z):calcd for C15H12NS[M+H]+:238.0685，found:238.0685。
example 13
The synthetic method of 5- (3-chlorophenyl) -3-phenylisothiazole of this example comprises the following synthetic routes:
the method comprises the following specific steps: respectively adding 1- (3-chlorphenyl) -3-phenylpropan-2-alkyne-1-ketone (120mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), stirring and reacting at 130 ℃ under the condition of N, N-dimethylacetamide (2mL) for 12 hours, adding ethyl acetate for quenching reaction, adding saturated saline water for washing, separating out an organic phase, repeatedly extracting an aqueous phase for 3 times by using ethyl acetate, combining the organic phases, adding anhydrous sodium sulfate for drying, removing a solvent by reduced pressure distillation, and separating by column chromatography to obtain a white solid (93.4mg, 77.8%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.01–7.97(m，2H)，7.75(s，1H)，7.67–7.64(m，1H)，7.56–7.51(m，1H)，7.48(t，J＝7.3Hz，2H)，7.44(d，J＝7.2Hz，1H)，7.40(d，J＝5.2Hz，2H).13C NMR(125MHz，CDCl3)δ168.4，166.6，135.2，134.6，132.6，130.5，129.5，129.4(2C)，128.9(2C)，126.6，124.8，118.2.HRMS(ESI)(m/z):calcd for C15H11ClNS[M+H]+:272.0295，found:272.0294。
example 14
The synthetic method of 5- (3-fluorophenyl) -3-phenylisothiazole of the embodiment comprises the following synthetic route:
the method comprises the following specific steps: respectively adding 1- (3-fluorophenyl) -3-phenylprop-2-alkyne-1-ketone (112mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), stirring and reacting at 130 ℃ under the condition of N, N-dimethylacetamide (2mL) for 12 hours, adding ethyl acetate for quenching reaction, adding saturated saline solution for washing, separating out an organic phase, repeatedly extracting an aqueous phase for 3 times by using ethyl acetate, combining the organic phases, adding anhydrous sodium sulfate for drying, removing a solvent by reduced pressure distillation, and separating by column chromatography to obtain a white solid (71.4mg, 63.8%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.98(d，J＝7.3Hz，2H)，7.70(s，1H)，7.64(dd，J＝8.6，5.2Hz，2H)，7.45(dt，J＝26.0，7.2Hz，3H)，7.16(t，J＝8.5Hz，2H)；13C NMR(125MHz，CDCl3)δ168.4，167.0(2C)，163.4(d，J＝250.2Hz,2C)，134.7，129.3，128.8，128.4(d，J＝8.4Hz)，127.3(d，J＝3.5Hz)，126.8(2C)，117.6，116.4(d，J＝22.0Hz，2C).HRMS(ESI)(m/z):calcd for C15H11FNS[M+H]+:256.0591，found:256.0591。
example 15
The synthetic method of 5- (3, 5-dichlorophenyl) -3-phenylisothiazole of this embodiment has the following synthetic route:
the method comprises the following specific steps: respectively adding 1- (3, 5-dichlorophenyl) -3-phenylpropan-2-alkyne 1-ketone (137mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), stirring and reacting at 130 ℃ under the condition of N, N-dimethylacetamide (2mL) for 12 hours, adding ethyl acetate for quenching reaction, adding saturated saline water for washing, separating out an organic phase, repeatedly extracting an aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate for drying, removing a solvent through reduced pressure distillation, and separating through column chromatography to obtain a white solid (75.8mg, 55.4%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.98(d，J＝8.4Hz，2H)，7.74(s，1H)，7.52(d，J＝1.8Hz，2H)，7.46(dt，J＝15.2，7.0Hz，3H)，7.41(t，J＝1.8Hz，1H).13C NMR(125MHz，CDCl3)δ168.5，165.0，135.9(2C)，134.4，133.6，129.5，129.2，128.9(2C)，126.8(2C)，124.9(2C)，118.6.HRMS(ESI)(m/z):calcd for C15H10Cl2NS[M+H]+:305.9906，found:305.9903。
example 16
The synthetic method of 5- (3, 5-dichlorophenyl) -3-phenylisothiazole of this embodiment has the following synthetic route:
the method comprises the following specific steps: respectively adding 3- (4-fluorophenyl) -1- (p-tolyl) prop-2-yn-1-one (119mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), stirring and reacting at 130 ℃ under the condition of N, N-dimethylacetamide (2mL) for 12 hours, adding ethyl acetate to carry out quenching reaction, adding saturated saline water to wash, separating out an organic phase, repeatedly extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate to dry, removing the solvent by reduced pressure distillation, and carrying out column chromatography separation to obtain a light yellow solid (95.7mg, 80.4%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.87(d，J＝8.0Hz，2H)，7.67(s，1H)，7.63(dd，J＝8.5，5.3Hz，2H)，7.30–7.25(m，2H)，7.16(t，J＝8.5Hz，2H)，2.41(s，3H)；13C NMR(125MHz，CDCl3)δ168.4，166.8，163.4(d，J＝250.1Hz)，139.4，132.1，129.5(2C)，128.4(d，J＝8.4Hz，2C)，127.3，126.7(2C)，117.5，116.3(d，J＝22.0Hz，2C)，21.4.HRMS(ESI)(m/z):calcd for C16H13FNS[M+H]+:270.0747，found:270.0745。
example 17
The synthetic method of 5- (3, 5-dichlorophenyl) -3-phenylisothiazole of this embodiment has the following synthetic route:
the method comprises the following specific steps: respectively adding 3- (2-chlorphenyl) -1- (p-tolyl) propyl-2-alkyne-1-ketone (127mg, 0.5mmo1), potassium ethylxanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), adding 2mL of N, N-dimethylacetamide, stirring and reacting at the reaction temperature of 130 ℃ for 12 hours, after the reaction is finished, adding ethyl acetate to carry out quenching reaction, adding saturated saline water to wash, separating out an organic phase, repeatedly extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate to dry, removing the solvent by reduced pressure distillation, and carrying out column chromatography separation to obtain a light yellow solid (105mg, 83.2%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.89(d，J＝8.1Hz，2H)，7.85(s，1H)，7.72–7.60(m，1H)，7.58–7.49(m，1H)，7.36(q，J＝6.9Hz，2H)，7.28(d，J＝8.0Hz,2H)，2.41(s，3H).13C NMR(125MHz，CDCl3)δ167.0，164.0，139.2，132.3，132.1，130.7，130.3，130.1，130.1，129.5(2C)，127.2，126.8(2C)，121.1，21.4.HRMS(ESI)(m/z):calcd for C16H13ClNS[M+H]+:286.0447，found:286.0445。
example 18
The synthetic route of the 3, 5-di (naphthalene-2-yl) isothiazole of this example is:
the method comprises the following specific steps: respectively adding 1, 3-di (naphthalene-2-yl) prop-2-yne-1-one (153mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), adding 2mL of N, N-dimethylacetamide, stirring and reacting at 130 ℃ for 12 hours, adding ethyl acetate to quench after the reaction is finished, adding saturated saline water for washing, separating out the organic phase, repeatedly extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate for drying, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a light yellow solid (122.7mg, 80.2%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.62(d，J＝8.3Hz，1H)，8.29(dd，J＝6.2，3.5Hz，1H)，7.98(dt，J＝6.2，3.1Hz，4H)，7.87(d，J＝7.0Hz，1H)，7.75(s，1H)，7.71(dd，J＝7.0，0.9Hz，1H)，7.60(dddd，J＝13.1，9.7，6.9，3.4Hz，6H)；13C NMR(125MHz，CDCl3)δ168.0，165.5,134.0，133.7，133.1，131.1，130.8，129.8，129.5，128.6，128.5，128.4，127.9，127.6，127.1，126.8，126.4，126.0，125.7，125.7，125.2，125.2，125.0.HRMS(ESI)(m/z):calcd for C23H16NS[M+H]+:338.0998found:338.0999。
example 19
The synthetic route of the 3, 5-di (thien-2-yl) isothiazole of this example is:
the method comprises the following specific steps: respectively adding 1, 3-di (thiophene-2-yl) prop-2-yne-1-one (108.5mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), adding 2mL of N, N-dimethylacetamide, stirring and reacting at the reaction temperature of 130 ℃ for 12 hours, adding ethyl acetate to carry out quenching reaction after the reaction is finished, adding saturated saline to wash, separating an organic phase, repeatedly extracting an aqueous phase by using ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate to dry, removing the solvent by reduced pressure distillation, carrying out column chromatography separation, and separating to obtain a brown solid (67.5mg, 62.2%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.53–7.48(m，2H)，7.39(dd，J＝10.6，5.1Hz，2H)，7.33(d，J＝3.5Hz，1H)，7.10(q，J＝4.4Hz，2H).13C NMR(125MHz，CDCl3)δ162.3，160.4，138.7，132.3，128.25，127.7，127.2，127.2，126.6，125.9.HRMS(ESI)(m/z):calcd for C11H8NS3[M+H]+:249.9813found:249.9812。
example 20
The synthesis of 5-phenyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) phenyl) isothiazole of this example is via the following route:
the method comprises the following specific steps: 1-phenyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) phenyl) propyl-2-yn-1-one (166mg, 0.5mmo1), potassium ethylxanthate (80mg, 0.5mmo1), ammonium iodide (145mg, 1mmo1) were added, 2mL of N, N-dimethylacetamide was added, the reaction was stirred at a reaction temperature of 130 ℃ for 12 hours, after completion of the reaction, ethyl acetate was added for quenching reaction, saturated brine was added for washing, the organic phases were separated, the aqueous phase was extracted with ethyl acetate repeatedly 3 times, the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography was performed to obtain a yellow liquid (118mg, 65%) after separation.
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.11(s，1H)，8.03(d，J＝7.3Hz，2H)，7.88(d，J＝7.4Hz，1H)，7.84(s，1H)，7.77(d，J＝7.8Hz，1H)，7.53–7.43(m，4H)，1.41(s，12H)；13C NMR(125MHz，CDCl3)δ168.2，136.0(2C)，134.8，132.6(2C)，130.4，129.4，129.2，128.8(2C)，128.6，126.9(2C)，117.7，84.2(2C)，24.9(4C).HRMS(ESI-TOF)(m/z):[M+Na]+calcd for C21H22BNNaO2S，385.1393，found 385.1394。
example 21
The synthetic method of 3- (4, 4-dimethylthiopyran-7-yl) -5-phenylisothiazole of this example comprises the following synthetic route:
the method comprises the following specific steps: respectively adding 3- (4, 4-dimethylthiochroman-7-yl) -1-phenylpropan-2-alkyne-1-ketone (153mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmol), adding 2mL of N, N-dimethylacetamide, stirring and reacting at the reaction temperature of 130 ℃ for 12 hours, after the reaction is finished, adding ethyl acetate for quenching reaction, adding saturated common salt water for washing, separating out an organic phase, repeatedly extracting an aqueous phase by using ethyl acetate for 3 times, combining the organic phase, adding anhydrous sodium sulfate for drying, removing the solvent by reduced pressure distillation, separating by column chromatography, and separating to obtain a yellow liquid (104mg, 62%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.99(d，J＝7.1Hz，2H)，7.69(s，1H)，7.61(d，J＝1.9Hz，1H)，7.50–7.39(m，3H)，7.32(dd，J＝8.2，2.0Hz，1H)，7.17(d，J＝8.2Hz，1H)，3.08(d，J＝12.2Hz，2H)，1.99(d，J＝12.2Hz，2H)，1.40(s，6H)；13C NMR(125MHz，CDCl3)δ168.4，168.2，142.8，134.9，134.5，129.2，128.8(2C)，127.3，126.8(2C)，126.7，124.4，124.1，116.8，37.1，33.1，30.0(2C)，23.1.HRMS(ESI-TOF)(m/z):[M+H]+calcd for C20H20NS2，338.1032，found:338.1026。
example 22
The synthetic method of 3- (4- (9H-carbazol-9-yl) phenyl) -5-phenylisothiazole of this example comprises the following synthetic route:
the method comprises the following specific steps: respectively adding 3- (4- (9H-carbazole-9-yl) phenyl) -1-phenylpropan-2-alkyne-1-ketone (188mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmol), adding 2ml of N, N-dimethylacetamide, stirring and reacting at the reaction temperature of 130 ℃ for 12 hours, after the reaction is finished, adding ethyl acetate for quenching reaction, adding saturated saline for washing, separating an organic phase, repeatedly extracting an aqueous phase by using ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate for drying, removing the solvent by reduced pressure distillation, separating by column chromatography, and separating to obtain a light yellow solid (145mg, 74%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.24(d，J＝8.4Hz，2H)，8.17(d，J＝7.8Hz，2H)，7.84(s，1H)，7.74–7.66(m，4H)，7.54–7.42(m，7H)，7.33(t，J＝7.4Hz，2H)；13C NMR(125MHz，CDCl3)δ168.7，167.3，140.6，138.4，133.7，130.8，129.7，129.3，128.3，127.2(2C)，126.6(2C)，126.0(2C)，123.5(2C)，120.3(2C)，120.1(2C)，117.5(2C)，109.8(2C).HRMS(ESI-TOF)(m/z):[M+H]+calcd for C27H19N2S，403.1263，found:403.1253。
example 23
The synthetic route of the 3-phenylisothiazole of this example is:
the method comprises the following specific steps: respectively adding 3-phenylpropyl aldehyde (58.5mg, 0.5mmo1), potassium ethylxanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), stirring and reacting at 130 ℃ under the condition of N, N-dimethylacetamide (2mL) for 12 hours, after the reaction is finished, adding ethyl acetate for quenching reaction, adding saturated saline for washing, separating out an organic phase, repeatedly extracting an aqueous phase for 3 times by using ethyl acetate, combining the organic phases, adding anhydrous sodium sulfate for drying, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain brown solid (47.5mg, 81.2%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ8.47(d，J＝1.6Hz，1H)，7.61(dd，J＝8.1，1.3Hz，2H)，7.47–7.37(m，4H).13C NMR(125MHz，CDCl3)δ167.3，158.2，130.7，129.5，129.2(2C)，126.7(2C)，119.8.HRMS(ESI)(m/z):calcd for C9H8NS[M+H]+:162.0372found:162.0371。
example 24
The synthetic route of the 5-methyl-3-phenylisothiazole of this example is:
the method comprises the following specific steps: respectively adding 4-phenylbut-3-alkyne-2-one (72mg, 0.5mmo1), potassium ethylxanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), adding 2mL of N, N-dimethylacetamide, stirring and reacting at 130 ℃ for 12 hours, adding ethyl acetate to carry out quenching reaction after the reaction is finished, adding saturated saline solution to wash, separating out an organic phase, repeatedly extracting an aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate to dry, removing the solvent through reduced pressure distillation, carrying out column chromatography separation, and separating to obtain a brown solid (59.2mg, 82.2%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.58(d，J＝6.8Hz，2H)，7.41(dt，J＝12.6，6.9Hz，3H)，7.20(s，1H)，2.53(s，3H).13C NMR(125MHz，CDCl3)δ167.9，167.4，131.0，129.4，129.2(2C)，126.5(2C)，120.4，19.1.HRMS(ESI)(m/z):calcd for C10H10NS[M+H]+:176.0532found:176.0530。
example 25
The synthetic route of the 5- (tert-butyl) -3-phenylisothiazole of this example is:
the method comprises the following specific steps: respectively adding 4, 4-dimethyl-1-phenylpent-1-alkyne-3-ketone (93mg, 0.5mmo1), potassium ethyl xanthate (80mg, 0.5mmo1) and ammonium iodide (145mg, 1mmo1), adding 2mL of N, N-dimethylacetamide, stirring and reacting at 130 ℃ for 12 hours, after the reaction is finished, adding ethyl acetate to quench the reaction, adding saturated saline solution to wash the reaction solution, separating out an organic phase, repeatedly extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding anhydrous sodium sulfate to dry, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a brown solid (87mg, 80%).
The test data of the product are as follows:
the characterization results of hydrogen spectrum and carbon spectrum of nuclear magnetic resonance are as follows:1H NMR(500MHz，CDCl3)δ7.59(d，J＝7.1Hz，2H)，7.41(dt，J＝14.6，7.0Hz，3H)，7.33(s，1H)，1.42(s，9H).13C NMR(125MHz，CDCl3)δ180.4，167.1，131.2，129.2，129.1(2C)，126.5(2C)，117.4，36.6，30.1(3C)；HRMS(ESI-TOF)(m/z):[M+H]+calcd for C13H16NS，218.0998，found:218.0993。
the embodiment of the invention provides a synthesis method of a 3, 5-disubstituted isothiazole compound, which takes a 1, 3-diphenyl-2-alkyne-1-ketone compound as a raw material, is free from transition metal catalysis, is heated and stirred under the condition of adding a solvent, and synthesizes the 3, 5-disubstituted isothiazole compound by a next pot method.
Comparative example 1
A synthetic method of 3, 5-disubstituted isothiazole compounds comprises the following synthetic route:
the method comprises the following specific steps: 5-aryl-4- ((ethylperoxy) -12-methyl) -1,2, 3-thiadiazole (98mg,0.5mmol), benzonitrile (103mg,1mmol), tris (triphenylphosphine) rhodium chloride (9.2mg, 2% mmol), 1' - (diphenylphosphine) ferrocene (14mg, 5% mmol) and 2mL of benzene chloride were added into a 25mL reaction tube, the mixture was stirred at 130 ℃ for 1 hour, after the reaction was completed, ethyl acetate was added for quenching reaction, a saturated saline solution was added for washing, the organic phase was separated, the aqueous phase was extracted with ethyl acetate for 3 times, the organic phase was combined, anhydrous sodium sulfate was added for drying, the solvent was removed by distillation under reduced pressure, column chromatography was performed, and a brown solid (65mg, 66%) was obtained after separation.
The foregoing detailed description of the synthesis and use of a 3, 5-disubstituted isothiazole compound provided herein will provide further details and embodiments, and the description of the embodiments is provided herein to assist in understanding the principles of the invention and its core concepts, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.
Claims (10)
1. A3, 5-disubstituted isothiazole compound, which is characterized in that: the structural formula of the compound is shown as a formula (II):
2. 3, 5-disubstituted isothiazole compound according to claim 1, wherein: the substituent of the phenyl derivative is halogen, C1-10 alkyl, alkoxy, sulfenyl or carbazolyl, and the number of the substituent on the benzene ring is 1-5; the heterocyclic group is furan, thiophene, pyrrole or naphthalene ring.
3. 3, 5-disubstituted isothiazole compound according to claim 1, wherein: the compound is any one of the following: 3, 5-diphenylisothiazole, 5- (3-chlorophenyl) -3-phenylisothiazole, 5- (3-fluorophenyl) -3-phenylisothiazole, 5- (3, 5-dichlorophenyl) -3-phenylisothiazole, 3, 5-di (naphthalen-2-yl) isothiazole, 3, 5-di (thien-2-yl) isothiazole, 5-phenyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) phenyl) isothiazole, 5-phenylisothiazole, and mixtures thereof, 3- (4, 4-dimethylthiopyran-7-yl) -5-phenylisothiazole, 3- (4- (9H-carbazol-9-yl) phenyl) -5-phenylisothiazole, 3-phenylisothiazole, 5-methyl-3-phenylisothiazole, 5- (tert-butyl) -3-phenylisothiazole.
4. A method for synthesizing 3, 5-disubstituted isothiazole compound according to any one of claims 1 to 3, wherein: mixing an alkynone compound with a general formula (I), a nitrogen source, a sulfur source and a solvent, and carrying out heating reaction to obtain a 3, 5-disubstituted isothiazole compound shown in a general formula (II):
5. The method of synthesis according to claim 4, characterized in that: the sulfur source is at least one of thioacetamide, copper dimethyldithiocarbamate, diisopropyl xanthogen disulfide, potassium ethyl xanthate or sodium sulfide.
6. The method of synthesis according to claim 4, characterized in that: the nitrogen source is at least one of ammonium iodide, ammonium chloride, ammonium bromide, ammonium acetate or ammonia water.
7. The method of synthesis according to claim 4, characterized in that: the solvent is at least one of N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide or dimethyl sulfoxide.
8. The method of synthesis according to claim 4, characterized in that: the temperature of the heating reaction is 90-130 ℃; the heating reaction time is 8-12 hours.
9. The method of synthesis according to claim 4, characterized in that: in the heating reaction, the molar ratio of the alkynone compound, the sulfur source and the nitrogen source is 1 (1.2-1.5) to 4-4.5.
10. Use of the 3, 5-disubstituted isothiazole compound according to any one of claims 1 to 3 for the preparation of a pharmaceutical or optoelectronic material.
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Non-Patent Citations (2)
| Title |
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| JIAN LI ET AL.,: "Transition Metal-Free Synthesis of Substituted Isothiazoles via Three-Component Annulation of Alkynones, Xanthate and NH4I", 《ADV. SYNTH. CATAL.》, vol. 363, no. 4, 9 December 2020 (2020-12-09), pages 2 - 3 * |
| ZHU-ZHU ZHANG ET AL.,: "Synthesis of Isoselenazoles and Isothiazoles from Demethoxylative Cycloaddition of Alkynyl Oxime Ethers", 《J.ORG.CHEM.》, vol. 86, 30 November 2020 (2020-11-30), pages 632 - 642 * |
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| CN118040044B (en) * | 2023-11-07 | 2024-09-13 | 南昌大学 | Electrolyte and lithium ion battery |
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