CN109053631B - Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol - Google Patents
Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol Download PDFInfo
- Publication number
- CN109053631B CN109053631B CN201810980752.7A CN201810980752A CN109053631B CN 109053631 B CN109053631 B CN 109053631B CN 201810980752 A CN201810980752 A CN 201810980752A CN 109053631 B CN109053631 B CN 109053631B
- Authority
- CN
- China
- Prior art keywords
- isothiocyanate
- reaction
- oxazine
- thioketone
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000002540 isothiocyanates Chemical class 0.000 title claims abstract description 30
- 125000005605 benzo group Chemical group 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 25
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- -1 trifluoromethylphenyl Chemical group 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 abstract description 4
- 239000001301 oxygen Substances 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 3
- 239000011593 sulfur Substances 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 18
- 239000000126 substance Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- LZETYGKTFLGIIN-UHFFFAOYSA-N 2-(4-benzylphenyl)sulfonylphenol Chemical compound C1(=CC=CC=C1)CC1=CC=C(C=C1)S(=O)(=O)C1=C(C=CC=C1)O LZETYGKTFLGIIN-UHFFFAOYSA-N 0.000 description 11
- 229940117953 phenylisothiocyanate Drugs 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- UQVQHVMEUNVRBR-UHFFFAOYSA-N 1,3-benzoxazine-2-thione Chemical class C1=CC=C2OC(=S)N=CC2=C1 UQVQHVMEUNVRBR-UHFFFAOYSA-N 0.000 description 2
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XQACWEBGSZBLRG-UHFFFAOYSA-N 1-bromo-4-isothiocyanatobenzene Chemical compound BrC1=CC=C(N=C=S)C=C1 XQACWEBGSZBLRG-UHFFFAOYSA-N 0.000 description 1
- MZZVFXMTZTVUFO-UHFFFAOYSA-N 1-chloro-4-isothiocyanatobenzene Chemical compound ClC1=CC=C(N=C=S)C=C1 MZZVFXMTZTVUFO-UHFFFAOYSA-N 0.000 description 1
- NFIUJHJMCQQYDL-UHFFFAOYSA-N 1-fluoro-4-isothiocyanatobenzene Chemical compound FC1=CC=C(N=C=S)C=C1 NFIUJHJMCQQYDL-UHFFFAOYSA-N 0.000 description 1
- VRPQCVLBOZOYCG-UHFFFAOYSA-N 1-isothiocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=S)C=C1 VRPQCVLBOZOYCG-UHFFFAOYSA-N 0.000 description 1
- NXHSSIGRWJENBH-UHFFFAOYSA-N 1-isothiocyanato-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(N=C=S)C=C1 NXHSSIGRWJENBH-UHFFFAOYSA-N 0.000 description 1
- QMCXTVATFCDODA-UHFFFAOYSA-N 2-(4-benzylphenyl)sulfonyl-4-methylphenol Chemical compound CC1=CC(=C(C=C1)O)S(=O)(=O)C1=CC=C(CC2=CC=CC=C2)C=C1 QMCXTVATFCDODA-UHFFFAOYSA-N 0.000 description 1
- MPFYLTOGHSUSKE-UHFFFAOYSA-N 2-[4-[(2-methylphenyl)methyl]phenyl]sulfonylphenol Chemical compound CC1=C(C=CC=C1)CC1=CC=C(C=C1)S(=O)(=O)C1=C(C=CC=C1)O MPFYLTOGHSUSKE-UHFFFAOYSA-N 0.000 description 1
- DZFKAXLNKZXNHD-UHFFFAOYSA-N 4-isothiocyanatobenzonitrile Chemical compound S=C=NC1=CC=C(C#N)C=C1 DZFKAXLNKZXNHD-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- QAADZYUXQLUXFX-UHFFFAOYSA-N N-phenylmethylthioformamide Natural products S=CNCC1=CC=CC=C1 QAADZYUXQLUXFX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011877 intramolecular nucleophilic addition Methods 0.000 description 1
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PYVFWTPEBMRKSR-UHFFFAOYSA-N tanaproget Chemical compound CN1C(C#N)=CC=C1C1=CC=C(NC(=S)OC2(C)C)C2=C1 PYVFWTPEBMRKSR-UHFFFAOYSA-N 0.000 description 1
- 229950001471 tanaproget Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention develops a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using 2-sulfonyl alkylphenol under alkalescent condition. 2-sulfonyl alkylphenol and isothiocyanate are used as substrates, a multifunctional benzo [1,3] oxazine-2-thioketone containing a nitrogen, oxygen and sulfur heterocyclic structure is synthesized by a one-step method, and the application of the reaction methodology of the isothiocyanate and o-QMs is expanded. The synthesis method provided by the invention can react at room temperature, has mild reaction conditions, good substrate universality, no need of a catalyst, simple and easily obtained alkaline reagent, convenient operation, economy and high efficiency; the method has high reaction activity, the yield reaches 92 percent, and the raw materials are completely converted; the product is convenient to separate, and the reaction is green and economical and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a synthesis method for synthesizing benzo [1,3] oxazine-2-thioketone by using isothiocyanate and 2-sulfonyl alkylphenol.
Background
The heterocyclic compound has wide biological activity and becomes a hotspot of research and development in the field of pharmaceutical research, wherein the oxazine-2-thione belongs to a polycyclic compound containing nitrogen, oxygen and sulfur heteroatoms, and the compound has biological activities of resisting cancer, resisting tumor, relieving pain, killing insects, sterilizing and the like. For example, the non-steroidal synthetic progestogen Tanaproget, which entered phase II clinical trials in 2010, may be used as an effective contraceptive in the future.
However, the current synthesis methods for oxazine-2-thione include substitution reaction using corresponding oxazine-2-ketone as substrate and Lawesson reagent (bioorg. Med. chem. Lett.2003,13, 1313-.
In 2015, Kazuhiro Kobayashi et al utilized 2- (1-isothiocyanato alkyl ester) phenol to undergo intramolecular cyclization under mild conditions to produce benzoxazine-2-thiones (Heterocycles,2016,93, 63-74). Although this reaction can efficiently synthesize benzoxazine-2-thione, the adoption of a synthetic strategy for intramolecular cyclization results in relatively limited substrates for the convenience of reaction; and the substrate 2- (1-isothiocyanatoalkyl ester) phenol is complicated to operate by a five-step synthetic process.
The isothiocyanate can participate in various organic reactions and is used for synthesizing various compounds containing sulfur, nitrogen and oxygen, in particular heterocyclic compounds. The C in-N ═ C ═ S in the isothiocyanate molecule has high electrophilicity and is capable of nucleophilic addition reaction with a nucleophile. For example, in the above synthetic scheme, the isothiocyanate group undergoes an intramolecular nucleophilic addition cyclization reaction. Because the classical reaction mode of the isothiocyanate is limited to nucleophilic addition reaction and is applied to the total synthesis of natural products containing glycosyl heterocycle and analogues thereof, the development of the isothiocyanate in the pharmaceutical chemical field is limited.
O-methylenequinone (o-QMs) is a transient, highly reactive intermediate that typically exists in two forms: a diradical species or a polarized zwitterion. However, o-QMs participates in catalyzing asymmetric [4+2]]The difficulty of the cycloaddition reaction is not only its short lifetime, but also includes the catalyst and o-QMs being too weak to promote the reaction. Also, among the various mechanisms currently used for the production of o-QMs, Lewis acids andthe acid-catalyzed substituent leaving operation method is simple and convenient, and the application range isThe precursor o-QMs, which contains acid sensitive functional groups (such as phenolic hydroxyl groups), is not suitable for these acidic catalysts. Therefore, under neutral or weakly alkaline conditions, compounds containing hydroxyl groups and the like are subjected to elimination reaction to generate o-QMs, and the type of synthetic reaction in which o-QMs participates can be effectively expanded.
Therefore, in order to realize efficient synthesis of benzoxazine-2-thione compounds and to expand the application of the reaction methodology of isothiocyanate and o-QMs, a new strategy for the synthetic transformation of benzo [1,3] oxazine-2-thione compounds is required.
Disclosure of Invention
The invention aims to provide a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using isothiocyanate and 2-sulfonyl alkylphenol. The method has the advantages of simple and practical operation, good yield, green and economical reaction and environmental friendliness.
The synthesis method provided by the invention specifically comprises the following steps:
2-sulfonyl alkyl phenol and isothiocyanate react under the action of an alkaline reagent to generate the benzo [1,3] oxazine-2-thioketone.
The benzo [1,3] oxazine-2-thioketone is a compound shown as a formula I:
in formula I, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl.
The above-mentioned 2-sulfonylalkylphenol is a compound represented by the formula II, and the above-mentioned isothiocyanate is a compound represented by the formula III:
in the formulas II and III, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl.
The alkaline reagent is any one of cesium carbonate, potassium carbonate, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and tetramethylguanidine.
The reaction is carried out in a solvent selected from dichloromethane, tetrahydrofuran and dioxane.
The molar ratio of the 2-sulfonylalkylphenol to the isothiocyanate is 2: 3.
The molar ratio of the alkaline reagent to the 2-sulfonyl alkylphenol is 2.5: 1; the amount of the solvent is 10L per mole of 2-sulfonylalkylphenol.
The above reaction was carried out at 25 ℃.
The reaction time is 1-16 h.
The invention provides a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by isothiocyanate and 2-sulfonyl alkylphenol, which comprises the following steps:
adding 0.2mmol of 2-sulfonylalkylphenol to 2mL of a solvent, followed by adding 0.3mmol of isothiocyanate and 0.5mmol of a basic agent to the solvent; controlling the temperature of the system to be 25 ℃ at room temperature, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete;
after reacting for 12h, separating a reaction product in the solution by using a silica gel column, and performing rotary evaporation and concentration to obtain a product.
The compounds to which the present invention relates may exist in the form of one or more stereoisomers. The various isomers include enantiomers, diastereomers, geometric isomers. It is within the scope of the present invention for these isomers to include mixtures of these isomers.
The technical scheme of the invention has the following beneficial effects: under the alkaline condition, p-toluenesulfonyl is removed from 2-sulfonyl alkyl phenol to generate o-QMs in situ, and the o-QMs and isothiocyanate undergo a [4+2] cycloaddition reaction. The reaction is subjected to a series cyclization reaction because isothiocyanate is a strong electron-deficient system and the difficulty of generating a reverse electron-demanding hetero Diels-Alder reaction is high. Since the properties of isothiocyanates are greatly influenced by substituent effects, different substituents result in reactions yielding different products, not just benzo [1,3] oxazine-2-thiones. The concrete expression is as follows: firstly, removing p-toluenesulfonyl from 2-sulfonylalkylphenol to generate o-QMs in situ, then attacking oxygen atom of o-QMs to the carbon of an electricity-deficient center of isothiocyanate to form two resonant transition state zwitterions TS2 and TS 2', and generating a product 3 in the form of TS2 when R is methoxy, methyl, fluorine, chlorine, bromine and trifluoromethyl substituted phenyl; when R is p-nitrophenyl, the product 4 is generated in the form of TS 2'; when R is p-cyanophenyl, both forms exist, and a mixed product is obtained. However, when R is an ester group, o-QMs is not undergone, but the phenolic hydroxyl group directly acts as a nucleophile to perform an addition reaction on the isothiocyanate to produce product 5.
The invention develops a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using 2-sulfonyl alkylphenol under alkalescent condition. 2-sulfonyl alkyl phenol and isothiocyanate are used as substrates, and a multifunctional benzo [1,3] oxazine-2-thioketone containing a nitrogen, oxygen and sulfur heterocyclic structure is synthesized by a one-step method. The method has the advantages of convenient and easily obtained reaction substrates, good substrate universality and no obvious influence of the position of a substrate substituent on the reaction yield. The alkaline reagent is simple and easy to obtain, convenient to operate, economical and efficient; the reaction activity is higher, and the raw material conversion is complete; the product is convenient to separate, and the reaction is green and economical and environment-friendly.
Detailed Description
The foregoing aspects of the present invention are further illustrated by the specific embodiments provided in the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples by those skilled in the art; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Taking 0.2mmol of 2- (α -phenyl p-toluenesulfonyl) phenol to a reaction bottle, sequentially adding 2mL of solvent, 0.3mmol of phenyl isothiocyanate and finally 0.5mmol of alkaline reagent, controlling the temperature of the system to be 25 ℃, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the raw materials are completely reacted.
After the reaction is finished, separating and purifying by using a silica gel column, and performing rotary evaporation on the purified product to obtain the target product.
Using the above reaction formula, 10 sets of parallel test groups were set up, using different alkaline reagents, solvents and reaction times. The alkaline reagents are respectively cesium carbonate Cs2CO3Potassium carbonate K2CO3Triethylamine TEA, 1, 8-diazabicyclo [5.4.0]]Undec-7-ene DBU, tetramethylguanidine TMG. The solvents are dichloromethane DCM, tetrahydrofuran THF and Dioxane respectively. The specific alkaline reagents, solvent types and concentrations used in the test groups are shown in table 1:
TABLE 1 reaction yield of 2- (α -Phenylp-toluenesulfonyl) phenol with phenylisothiocyanate
Serial number | Alkaline reagent | Solvent(s) | Reaction time (h) | Yield (%) |
1 | Cs2CO3 | DCM | 12 | 92 |
2 | Cs2CO3 | Dioxane | 12 | 86 |
3 | Cs2CO3 | THF | 12 | 79 |
4 | TEA | DCM | 12 | 63 |
5 | DBU | DCM | 12 | 54 |
6 | TMG | DCM | 12 | 62 |
7 | K2CO3 | DCM | 12 | 75 |
8 | Cs2CO3 | DCM | 1 | 19 |
9 | Cs2CO3 | DCM | 8 | 72 |
10 | Cs2CO3 | DCM | 16 | 80 |
Note: the yield is an isolated yield.
According to the analysis of the results of the parallel tests, the reduction or increase of the reaction time can lead to the reduction of the yield of the reactant, and the selection of the metal salt reagent and the organic alkaline reagent in the reaction can obtain higher yield of the target product.
Example 2
According to the procedure of example 1, 2- (α -phenyl-p-toluenesulfonyl) phenol was reacted with 4-cyanophenyl isothiocyanate, 4-nitrophenyl isothiocyanate and ethyl isothiocyanatecarboxylate, respectively, in the same reaction system as the reagents, in the presence of 0.5mmol of cesium carbonate in 2mL of DCM as a solvent, under continuous stirring at 25 ℃ for 12 hours, to complete the reaction.
According to the analysis of the test results, one of the reaction raw materials is isothiocyanate with different electric substituents, and the yield of benzo [1,3] oxazine-2-thioketone is obviously reduced due to different addition products obtained by the [4+2] cycloaddition of the isothiocyanate and o-QMs in the reaction process.
In the following examples 3 to 16, according to the procedure of example 1, the starting material 1-sulfonylalkylphenol and isothiocyanate were 0.2mmol and 0.3mmol, respectively, the amount of the basic agent was 0.5mmol of cesium carbonate, and 2mL of DCM was used as a solvent, and the reaction was continued with stirring at 25 ℃ for 12 hours to complete the reaction.
Example 3
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H15NOS
Molecular weight: 318.4126
yield: 92 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.31(m,8H),7.21–7.14(m,3H),7.04(d,J=7.1Hz,3H),5.69(s,1H).13C NMR(125MHz,CDCl3)δ=182.9,147.9,143.8,140.2,129.6,129.5,129.2,128.9,128.5,127.6,127.4,126.2,125.5,121.8,116.5,67.1.HRMS(ESI)Calcd forC20H15NOS[M+H]+:318.4121,Found:318.4126.
Example 4
The raw materials are 4-methyl-2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4386
yield: 81 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.30(m,6H),7.21-7.15(m,4H),7.02(s,2H),6.81(s,1H),5.63(s,1H),2.28(s,3H).13C NMR(125MHz,CDCl3)δ=183.1,146.0,143.9,140.3,135.3,130.2,129.5,129.2,128.9,128.4,127.6,127.4,126.3,121.4,116.2,67.2,20.8.HRMS(ESI)Calcdfor C21H17NOS[M+H]+:332.4381,Found:332.4386.
Example 5
The raw materials are 2-methoxy-6- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
yield: 62 percent of
1H NMR(500MHz,CDCl3)δ7.31-7.26(m,6H),7.20(s,2H),7.08–7.02(m,3H),6.90(d,J=8.0Hz,1H),6.58(d,J=7.6Hz,1H),5.65(s,1H),3.94(s,3H).13C NMR(125MHz,CDCl3)δ=182.5,147.0,143.8,140.1,137.6,129.4,129.1,128.8,128.3,127.5,127.2,125.5,122.8,117.0,111.5,66.9,56.0.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 6
The raw materials are 4-chloro-2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14ClNOS
Molecular weight: 352.8577
yield: 71 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.30(m,7H),7.26(d,J=3.2Hz,1H),7.16(dd,J=6.5,3.0Hz,2H),7.00(d,J=2.2Hz,3H),5.62(s,1H).13C NMR(125MHz,CDCl3)δ=182.4,146.4,143.6,139.5,130.5,129.7,129.6,129.4,129.2,128.6,127.5,127.3,126.0,123.3,118.0,66.7.HRMS(ESI)Calcd for C20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Example 7
The raw materials are 2- (α -m-methylphenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
yield: 83 percent
1H NMR(500MHz,CDCl3)δ7.38–7.28(m,5H),7.21–7.10(m,3H),7.02(d,J=7.2Hz,3H),6.96(d,J=8.7Hz,2H),5.62(s,1H),2.29(s,3H).HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 8
The raw materials are 2- (α -p-benzyloxy-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
yield: 86 percent of the total weight
1H NMR(500MHz,CDCl3)δ7.32–7.14(m,5H),7.04(t,J=7.2Hz,1H),6.96(d,J=8.7Hz,2H),6.90(d,J=7.7Hz,3H),6.72(d,J=8.6Hz,2H),5.55(s,1H),3.67(s,3H).HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 9
The raw materials are 2- (α -o-methylphenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
yield: 71 percent of
1H NMR(500MHz,CDCl3)δ7.36–7.28(m,5H),7.24–7.14(m,4H),7.14–7.02(m,3H),6.90(d,J=7.6Hz,1H),6.05(s,1H),1.97(s,3H).HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 10
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol, p-toluene isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
yield: 83 percent
1H NMR(500MHz,CDCl3)δ7.38–7.27(m,5H),7.22–7.09(m,5H),7.01(d,J=7.5Hz,1H),6.89(d,J=7.0Hz,2H),5.65(s,1H),2.34(s,3H).13C NMR(125MHz,CDCl3)δ=183.0,147.9,141.3,140.3,138.5,130.2,129.5,129.2,128.9,127.4,127.2,126.2,125.4,121.8,116.5,67.1,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 11
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and m-toluene isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
yield: 73 percent
1H NMR(500MHz,CDCl3)δ7.29–7.17(m,6H),7.17–7.02(m,5H),6.94(d,J=7.3Hz,1H),6.74(d,J=34.9Hz,2H),5.58(s,1H),2.20(s,3H).13C NMR(125MHz,CDCl3)δ=182.8,147.9,143.7,140.2,139.6,129.5,129.2,129.2,129.1,128.8,127.8,127.3,126.1,125.4,124.6,121.8,116.4,67.0,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 12
The raw materials are 2- (α -phenyl p-toluenesulfonyl) phenol, 4-methoxyphenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
yield: 74 percent
1H NMR(500MHz,CDCl3)δ7.39–7.28(m,5H),7.21–7.11(m,3H),7.01(d,J=7.2Hz,1H),6.92(s,2H),6.83(d,J=8.7Hz,2H),5.64(s,1H),3.79(s,3H).13C NMR(125MHz,CDCl3)δ=183.2,159.1,147.9,140.3,136.7,129.5,129.2,128.9,128.6,127.5,126.2,125.4,121.8,116.5,114.6,67.3,55.4.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 13
The raw material is 2- (α -phenyl-p-toluenesulfonyl) phenol, 4-fluorophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14FNOS
Molecular weight: 336.4031
yield: 85 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.29(m,5H),7.17–7.14(m,3H),7.01(d,J=7.8Hz,5H),5.64(s,1H).13C NMR(125MHz,CDCl3)δ=183.0,161.9(d,J=249.1Hz),147.7,139.7(d,J=2.5Hz),139.6,129.6,129.5(d,J=7.0Hz),129.2,129.0,127.4,126.2,125.5,121.5,116.6,116.4,67.1.HRMS(ESI)Calcd for C20H14FNOS[M+H]+:336.4026,Found:336.4031.
Example 14
Starting materials 2- (α -phenyl-p-toluenesulfonyl) phenol, 4-chlorophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14ClNOS
Molecular weight: 352.8577
yield: 94 percent of
1H NMR(500MHz,CDCl3)δ7.38–7.29(m,7H),7.17–7.13(m,3H),7.01(d,J=7.6Hz,1H),6.95(d,J=7.5Hz,2H),5.63(s,1H).13C NMR(125MHz,CDCl3)δ=182.9,147.8,142.2,139.9,134.3,129.8,129.7,129.3,129.1,127.4,126.3,125.6,121.5,116.5,67.1.HRMS(ESI)Calcd forC20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Example 15
The raw materials are 2- (α -phenyl p-toluenesulfonyl) phenol, 4-bromophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14BrNOS
Molecular weight: 397.3087
yield: 81 percent of
1H NMR(500MHz,CDCl3)δ7.47(d,J=7.9Hz,2H),7.40–7.27(m,5H),7.24–7.12(m,3H),7.03(d,J=7.5Hz,1H),6.90(d,J=6.8Hz,2H),5.65(s,1H).13C NMR(125MHz,CDCl3)δ=182.8,147.7,142.7,139.8,132.8,129.7,129.4,129.3,129.1,127.3,126.2,125.6,122.4,121.4,116.4,67.0.HRMS(ESI)Calcd for C20H14BrNOS[M+H]+:397.3082,Found:397.3087.
Example 16
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and benzyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
yield: 73 percent
1H NMR(500MHz,CDCl3)δ7.40–7.31(m,6H),7.30–7.20(m,4H),7.05(t,J=7.6Hz,1H),6.90(d,J=7.2Hz,1H),6.32(d,J=15.1Hz,1H),5.34(s,1H),4.10(d,J=15.2Hz,1H).13CNMR(125MHz,CDCl3)δ=183.6,147.6,140.0,134.6,129.5,129.4,129.0,128.3,128.2,126.9,126.4,126.3,126.3,125.3,116.3,61.2,56.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (6)
1. A synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by isothiocyanate and 2-sulfonyl alkyl phenol is characterized in that: 2-sulfonyl alkyl phenol and isothiocyanate react under the action of an alkaline reagent to generate the benzo [1,3] oxazine-2-thioketone;
the benzo [1,3] oxazine-2-thioketone is a compound shown in a formula I:
in formula I, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl;
the 2-sulfonyl alkyl phenol is a compound shown as a formula II, and the isothiocyanate is a compound shown as a formula III:
in the formulas II and III, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl;
the alkaline reagent is any one of cesium carbonate, potassium carbonate, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and tetramethylguanidine.
2. The method of synthesis according to claim 1, characterized in that: the reaction is carried out in a solvent, wherein the solvent is any one of dichloromethane, tetrahydrofuran and dioxane.
3. The method of synthesis according to claim 2, characterized in that: the molar ratio of the 2-sulfonylalkylphenol to the isothiocyanate is 2: 3.
4. The method of synthesis according to claim 3, characterized in that: the molar ratio of the alkaline reagent to the 2-sulfonyl alkylphenol is 2.5: 1; the amount of the solvent is 10L per mole of 2-sulfonylalkylphenol.
5. The method of synthesis according to claim 4, characterized in that: the reaction is carried out at 25 ℃.
6. The method of synthesis of any one of claims 1-5, wherein: the method specifically comprises the following steps: adding 0.2mmol of 2-sulfonylalkylphenol to 2mL of a solvent, followed by adding 0.3mmol of isothiocyanate and 0.5mmol of a basic agent to the solvent; controlling the temperature of the system to be 25 ℃ at room temperature, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete;
after reacting for 12h, separating a reaction product in the solution by using a silica gel column, and performing rotary evaporation and concentration to obtain a product.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810980752.7A CN109053631B (en) | 2018-08-27 | 2018-08-27 | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810980752.7A CN109053631B (en) | 2018-08-27 | 2018-08-27 | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109053631A CN109053631A (en) | 2018-12-21 |
CN109053631B true CN109053631B (en) | 2020-06-09 |
Family
ID=64756138
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810980752.7A Expired - Fee Related CN109053631B (en) | 2018-08-27 | 2018-08-27 | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109053631B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115109006A (en) * | 2022-05-20 | 2022-09-27 | 上海大学 | 3-substituted-1, 2-benzoxazine-4-ketone compound and preparation method thereof |
-
2018
- 2018-08-27 CN CN201810980752.7A patent/CN109053631B/en not_active Expired - Fee Related
Non-Patent Citations (2)
Title |
---|
Direct amination of 2-(1-tosylalkyl)phenols with aqueous ammonia:a metal-free synthesis of primary amines;B. Wu et al.;《Tetrahedron Letters》;20150119;第56卷;第1135–1137页 * |
Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains;S. Vojacek et al.;《Arch. Pharm. Chem. Life Sci.》;20171231;第350卷;第e1700097页 * |
Also Published As
Publication number | Publication date |
---|---|
CN109053631A (en) | 2018-12-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH06298731A (en) | Production of heterocyclic compound | |
SI20071A (en) | Asymmetric synthesis of benzoxazinones | |
Reddy et al. | Di-n-butyl ammonium chlorosulfonate ionic liquids as an efficient and recyclable catalyst for the synthesis of 1, 4-dihydrobenzo [4, 5] imidazo [1, 2-a] pyrimidine-3-carboxylates under solvent-free ultrasound irradiation | |
CN108863890B (en) | 4-pyrroline-2-ketone derivative and preparation method thereof | |
CN109053631B (en) | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol | |
Siddiqui et al. | Ionic liquid promoted spiroannulation via hetero-Michael addition and intramolecular heterocyclisation | |
CN112321583B (en) | Synthesis method of 1,2, 4-thiadiazole compound | |
CN113214112A (en) | Beta-amino acrylate substituted acetonitrile compound and preparation method and application thereof | |
Wang et al. | DMAP-promoted in situ activation of bromoacetic acid as a 2-carbon synthon for facile synthesis of pyridines and fused pyridin-2-ones | |
CN108440483B (en) | 3, 4-dihydrooxy-2 (7H) -ketone and preparation method thereof | |
CN111362795B (en) | Preparation method of substituted butyrate derivatives | |
CN108610306B (en) | Synthetic method of 2H-1, 4-thiazine-3 (4H) -ketone derivative | |
Watzke et al. | First Synthesis of Bi‐and Tricyclic α, β‐Unsaturated δ‐Oxacaprolactams from Cyclic Imines via Ring‐Closing Metathesis | |
CN107513056A (en) | A kind of synthetic method of the quinolines of the group containing tetrahydrofuran | |
CN109879832B (en) | 4-alkoxy-2-aryl mercaptomorpholine-3, 5-dione compound and preparation method thereof | |
CN113429409A (en) | Sulfur-containing polysubstituted indolizine compound and preparation method thereof | |
JPS6236374A (en) | Production of thiotetroic acid | |
KR100586671B1 (en) | Process for producing 5-substituted oxazole compounds and 5-substituted imidazole compounds | |
Chen et al. | Synthesis of N‐Phenyl‐N′‐pyrimidylurea Derivatives by Selenium‐or Selenium Dioxide‐Catalyzed Reductive Carbonylation of Nitroaromatics | |
Jagrut et al. | An improved synthetic route for the synthesis of sulfonamides | |
Banerjee et al. | Transition metal-free, base mediated one-pot approach for the construction of the benzo [b][1, 4, 5] oxathiazepine 1-oxide core | |
Fodor et al. | Preparation and ring transformation of isomeric β-lactam derivatives of bicyclic 1, 3-thiazines | |
WO1999046252A1 (en) | Process for producing oxazolidin-2-one derivatives | |
JP3740886B2 (en) | Process for producing oxazolidin-2-ones | |
US6476236B1 (en) | Synthesis of 2-cyanoaziridine-1-carboxamide |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200609 |