CN111039837B - Biaryl axial chiral alkyl sulfide and synthesis method and application thereof - Google Patents
Biaryl axial chiral alkyl sulfide and synthesis method and application thereof Download PDFInfo
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- -1 alkyl sulfide Chemical compound 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 125000005841 biaryl group Chemical group 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 150000005347 biaryls Chemical group 0.000 claims description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 12
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 125000004185 ester 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000003446 ligand Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HLPYVXKTMXQMID-PMACEKPBSA-N (4R)-4-phenyl-2-[1-[(4R)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]cyclopentyl]-4,5-dihydro-1,3-oxazole Chemical compound C1CCC(C1)(C1=N[C@@H](CO1)c1ccccc1)C1=N[C@@H](CO1)c1ccccc1 HLPYVXKTMXQMID-PMACEKPBSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- DDAPSNKEOHDLKB-UHFFFAOYSA-N 1-(2-aminonaphthalen-1-yl)naphthalen-2-amine Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3N)=C(N)C=CC2=C1 DDAPSNKEOHDLKB-UHFFFAOYSA-N 0.000 description 1
- VCNYPJMEQHTAHS-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=CC(Cl)=C1 VCNYPJMEQHTAHS-UHFFFAOYSA-N 0.000 description 1
- RZJGKPNCYQZFGR-UHFFFAOYSA-N 1-(bromomethyl)naphthalene Chemical compound C1=CC=C2C(CBr)=CC=CC2=C1 RZJGKPNCYQZFGR-UHFFFAOYSA-N 0.000 description 1
- ABMKWMASVFVTMD-UHFFFAOYSA-N 1-methyl-2-(2-methylphenyl)benzene Chemical compound CC1=CC=CC=C1C1=CC=CC=C1C ABMKWMASVFVTMD-UHFFFAOYSA-N 0.000 description 1
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical compound C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- FLFWJIBUZQARMD-UHFFFAOYSA-N 2-mercapto-1,3-benzoxazole Chemical compound C1=CC=C2OC(S)=NC2=C1 FLFWJIBUZQARMD-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-WBJZHHNVSA-N methoxybenzene Chemical group CO[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 RDOXTESZEPMUJZ-WBJZHHNVSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- ULAQISQDFQAUCH-UHFFFAOYSA-N trifluoromethanesulfonic acid hydroiodide Chemical compound I.OS(=O)(=O)C(F)(F)F ULAQISQDFQAUCH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
- C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0218—Sulfides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a biaryl axial chiral alkyl sulfide (III) and a synthesis method and application thereof, the biaryl axial chiral alkyl sulfide compound is efficiently synthesized by a nucleophilic substitution reaction of optically pure biaryl axial chiral heterocyclic sulfide, halogenated alkane and the like, the reaction can be carried out in the air, the operation is simple, the reaction condition is mild, the post-treatment is convenient, the raw materials are easy to obtain, the total yield is high, the ee value of the obtained biaryl axial chiral compound is 99% at most, and the yield can be as high as 99%;
Description
Technical Field
The invention relates to a biaryl axial chiral alkyl sulfide, a synthesis method thereof and application of the biaryl axial chiral alkyl sulfide as a chiral catalyst in asymmetric reaction.
Background
Biaryl-like axial chiral compounds are widely found in natural products, bioactive molecules, chiral ligands, drug molecules and liquid crystal materials due to their specific chemical structures (angelw. chem. int. ed.,2005,44, 5384.; chem. rev.,2011,111,563.; nat. prod. rep.,2015,32, 1562.; future. med. chem.2018,10,409.). As a chiral ligand, biaryl axial chiral compounds play an important role in various asymmetric catalytic reaction systems, for example, classical chiral ligands BINOL, BINAM and BINAP all contain biaryl axial chiral structural frameworks. Sulfur-containing compounds are a class of important structures that are widely found in fine chemicals, natural products, biologically active molecules, drug molecules, material molecules and chiral molecules, and the synthesis of such compounds has been a hot research direction in the organic chemistry community (Martino, G.D.; Regina, G.L.; Coluccia, A.; Edler, M.C.; et al.J.Med.Chem.2004,47,6120.Thomas, G.L.; Spandel, R.J.; Glansdorp, F.G.; Welch, M.; et al.Angew.Chem, int.Ed.2008,47,2808.). As bioactive molecules, the structure plays an important role in the fields of antibiosis, antivirus, antitumor and the like. In addition, as a chiral ligand, the biaryl axial chiral thioether structure can complete asymmetric catalytic reaction by coordination of sulfur and various metals such as palladium, ruthenium, rhodium and the like, and the characteristic has important application value in chiral molecule synthesis (Mellah, M.; Voituriez, A.; Schulz, E.chem.Rev.2007,107, 5133.).
At present, the synthesis of the axial chiral compound mainly comprises the following three methods, (1) two molecular aryl is obtained by oxidation cross coupling reaction; (2) constructing one of the aromatic rings by using an asymmetric synthesis method; (3) a single chiral structure is obtained by kinetic asymmetric resolution. In terms of synthesis angle, the above synthesis method has harsh reaction conditions, the normal temperature of the cross-coupling reaction is high, and the asymmetric resolution method is often inefficient by using a noble metal as a catalyst. The synthesis method takes the optically pure biaryl axial chiral heterocyclic sulfide as a raw material, and the optically pure biaryl axial chiral heterocyclic sulfide and halogenated alkane and the like are converted into biaryl axial chiral alkyl sulfide compounds with rich structural types through simple nucleophilic substitution reaction. The method is a great breakthrough to the conventional synthetic method in terms of the richness of raw material sources, the atom economy of reaction, the simplicity of the synthetic method and the structural novelty, diversity and wide applicability of the synthetic product. Therefore, the method has certain application value.
Disclosure of Invention
The invention efficiently synthesizes biaryl axial chiral alkyl sulfide compounds through nucleophilic substitution reaction of optical pure biaryl axial chiral heterocyclic sulfide and halogenated alkane and the like. The reaction can be carried out in the air, and the method is simple to operate and convenient for post-treatment. Solves the problem that the prior synthesis of biaryl axial chiral alkyl sulfide needs expensive reagents or has low synthesis efficiency.
The technical scheme of the invention is as follows:
a biaryl axial chiral alkyl sulfide represented by formula (III):
in the formula (III), the compound represented by the formula (III),
R1、R2each independently is: C5-C10 aryl, substituted C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl, hetero C2-C6 alkyl, unsaturated C2-C6 alkyl, nitro, trifluoromethyl, hydroxyl, ester group or halogen; preference is given, for example: methyl, ethyl, propyl, chloro or fluoro;
R5comprises the following steps: C5-C10 aryl, substituted C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl, hetero C2-C6 alkyl or unsaturated C2-C6 alkyl; preference is given, for example: methyl, ethyl, isopropyl, cyclopentyl, phenyl, bromophenyl, or naphthyl;
n is: an integer of 0 to 4.
A synthetic method of biaryl axial chiral alkyl sulfide (III) comprises the following steps:
uniformly mixing an optically pure biaryl axial chiral sulfur-containing heterocyclic compound (I), a compound (II), an alkaline substance and a solvent ethanol, reacting for 2-4 h at room temperature (20-30 ℃), and then carrying out post-treatment on a reaction solution to obtain a product biaryl axial chiral alkyl sulfide (III);
wherein the ratio of the amounts of the compound (I), the compound (II) and the alkaline substance is 1: 1-3: 1-3;
the alkaline substance is sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide;
the volume usage amount of the solvent ethanol is 10-30 mL/mmol based on the substance of the compound (I);
the post-treatment method of the reaction liquid comprises the following steps: after the reaction is finished, concentrating the reaction solution, and performing column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate is (100-5): 1 as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain target product (III);
the reaction formula is as follows:
in the formula (I) or (II),
R1、R2、R5n is as defined in formula (III);
R3、R4each independently is: hydrogen, (hetero) C5-C10 aryl, substituted (hetero) C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl, hetero-C2-C6 alkyl, unsaturated C2-C6 alkyl, nitro, ester group or halogen; preference is given, for example: hydrogen, phenyl or p-nitrophenyl, or R3、R4Together form a benzene ring, a methyl benzene ring, a chlorobenzene ring or a methoxy benzene ring;
x is: oxygen or sulfur;
y is: chlorine, bromine, iodine, methylsulfonyl or p-toluenesulfonyl.
The biaryl axial chiral alkyl sulfide (III) can be used as a chiral catalyst to be applied to asymmetric reaction.
In the invention, the substrate optical pure biaryl axial chiral sulfur-containing heterocyclic compound (I) is prepared by the following method:
uniformly mixing a diaryl cyclic iodonium salt compound (A), a mercapto heterocyclic compound (B), copper acetate, a chiral ligand, sodium carbonate and a solvent dichloromethane, stirring and reacting at-5 ℃ for 6-12 h, and then carrying out post-treatment on a reaction solution to obtain a compound (I);
the ratio of the diaryl cyclic iodonium salt compound (A) to the mercapto heterocyclic compound (B) to the copper acetate to the chiral ligand to the sodium carbonate is 1: 1: 0.005-0.05: 0.01-0.1: 2-4;
the volume usage of the solvent dichloromethane is 10-30 mL/mmol based on the substance amount of the mercapto heterocyclic compound (B);
the chiral ligand is a chiral oxazoline ligand, and specifically comprises the following components: (4R,4'R) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-phenyl-4, 5-dihydrooxazole);
the post-treatment method of the reaction liquid comprises the following steps: after the reaction is finished, concentrating the reaction solution, performing column chromatography, and performing column chromatography by using a petroleum ether-ethyl acetate volume ratio of 100-5: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent and drying to obtain a compound (I);
the reaction formula is as follows:
in the formula (A) or (B),
R1、R2、R3、R4and X is as defined in formula (I).
The invention has the following advantages: the method has the advantages of simple reaction system, mild reaction conditions, easily obtained raw materials, particularly compounds containing halogenated alkane, no need of multi-step preparation of substrates, simple post-treatment and higher total yield.
The innovation point of the invention is that the method for efficiently synthesizing the biaryl axial chiral alkyl sulfide by using the optically pure biaryl axial chiral heterocyclic sulfide, the halogenated alkane and the like through simple nucleophilic substitution reaction in the air at a certain temperature. The ee value of the biaryl axial chiral compound obtained by the invention is 99 percent at most.
Detailed Description
The present invention is further illustrated by the following specific examples, but the scope of the invention is not limited thereto.
In the following examples, the synthesis of starting material Ia was as follows:
2-mercaptobenzoxazole (31.7mg, 0.21mmol), 2,2 '-dimethyl- [1,1' -biphenyl ] -cyclic iodonium trifluoromethanesulfonate (91.2mg, 0.2mmol), copper acetate (0.9mg, 2.5 mol%), (4R,4'R) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-phenyl-4, 5-dihydrooxazole) (3.3mg, 4.5 mol%), sodium carbonate (63.6mg, 0.6mmol) were dissolved in 4mL of dichloromethane and the solution was stirred at 0 ℃ for 12 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 30:1 elution, concentration to give 90.5mg, 99% yield.
1H NMR(500MHz,CDCl3)δ＝7.83–7.78(m,1H),7.72(dd,J＝7.0,2.0Hz,1H),7.65–7.61(m,1H),7.45–7.37(m,3H),7.28(pd,J＝7.4,1.5Hz,2H),7.23(dt,J＝7.6,0.9Hz,1H),7.00(t,J＝7.7Hz,1H),2.05(s,3H),2.04(s,3H)ppm.13C NMR(126MHz,CDCl3) D 162.6,151.7,145.8,143.0,142.0,138.1,137.5,136.7,131.9,131.2,130.0,129.6,128.9,127.9,124.4,124.3,119.2,110.0,101.0,21.3,20.1ppm HRMS m/z (ESI) calculated C21H17INOS[M+H]+458.0070, found 458.0074.ee values were determined by HPLC using a chiral IC column (n-hexane: isopropanol 97:3,0.6mL/min,254nm, 99% ee); t is tr＝8.77min(S)，tr＝9.57min(R).
Example 1
Synthesis of Compound IIIa
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), methyl iodide (42.6mg, 0.3mmol), and potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol, and the solution was stirred at room temperature for reaction for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 80:1 elution, concentration yielded 67.3mg, 95% yield.
1H NMR(500MHz,CDCl3)δ＝7.86–7.79(m,1H),7.33(t,J＝7.8Hz,1H),7.29(dt,J＝7.5,1.0Hz,1H),7.16–7.08(m,2H),7.01(t,J＝7.7Hz,1H),2.40(s,3H),2.06(s,3H),1.95(s,3H)ppm.13C NMR(126MHz,CDCl3) The Δ ═ 143.2,141.2,138.4,137.7,136.9,136.0,130.0,129.4,128.3,126.3,121.8,101.4,21.2,19.7,15.4ppm. ee values were determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.6mL/min,254nm, 99% ee); t is tr＝6.23min(S),tr＝6.49min(R).
The structural formula of the product is as follows:
example 2
Synthesis of Compound IIIb
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), 2-iodopropane (51.0mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 80:1 elution, concentration gave 68.0mg, 89% yield.
1H NMR(500MHz,CDCl3)δ＝7.80(ddd,J＝8.0,1.2,0.7Hz,1H),7.31–7.23(m,3H),7.13–7.08(m,1H),7.00(t,J＝7.7Hz,1H),3.51(hept,J＝6.7Hz,1H),2.04(s,3H),1.93(s,3H),1.31(dd,J＝11.5,6.6Hz,6H)ppm.13C NMR(126MHz,CDCl3) δ 143.6,142.7,138.1,136.7,136.4,136.1,129.8,129.1,128.0,126.8,124.8,101.4,35.4,23.0,22.9,21.3,19.9ppm hrms m/z (esi): calculated value C17H19INaS[M+Na]+405.0144, found 405.0161.ee value determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.4mL/min,254nm, 99% ee); t is tr＝7.72min(S),tr＝9.09min(R).
The structural formula of the product is as follows:
example 3
Synthesis of Compound IIIc
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), bromocyclopentane (44.7mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 68.5mg, 84% yield.
1H NMR(500MHz,CDCl3)δ＝7.80(d,J＝7.9Hz,1H),7.30–7.23(m,3H),7.08(ddd,J＝7.2,1.6,0.8Hz,1H),7.00(t,J＝7.7Hz,1H),3.71–3.62(m,1H),2.15–2.06(m,2H),2.05(s,3H),1.92(s,3H),1.73(ddq,J＝12.8,8.1,2.6Hz,2H),1.67–1.51(m,4H)ppm.13C NMR(126MHz,CDCl3) δ 143.4,141.8,138.2,137.5,136.8,136.1,129.9,129.2,128.0,126.3,124.2,101.4,43.5,33.4,33.3,25.0,21.2,19.8ppm hrms m/z (esi): calculated value C19H22IS[M+H]+409.0481, found 409.0493.ee value determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.4mL/min,254nm, 99% ee); t is tr＝9.90min(R),tr＝11.04min(S).
The structural formula of the product is as follows:
example 4
Synthesis of Compound IIId
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), beta-bromophenylethane (55.5mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 69.3mg, 78% yield.
1H NMR(500MHz,CDCl3)δ＝7.87–7.79(m,1H),7.36–7.28(m,4H),7.27–7.19(m,4H),7.14(dt,J＝7.4,1.0Hz,1H),7.02(t,J＝7.8Hz,1H),3.15–3.08(m,2H),2.97–2.90(m,2H),2.07(s,3H),1.97(s,3H)ppm.13C NMR(126MHz,CDCl3)δ＝143.3,142.2,140.5,138.3,136.8,136.4,135.9,129.9,129.3,128.5,128.4,128.2,126.9,126.4,123.3,101.4,35.6,33.4,21.3,19.9ppm.HRMS m/z(ESI) The method comprises the following steps Calculated value C22H22IS[M+H]+445.0481, found 445.0492.ee value determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.5mL/min,254nm, 99% ee); t is tr＝5.67min(S),tr＝7.08min(R).
The structural formula of the product is as follows:
example 5
Synthesis of Compound IIIe
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), benzyl bromide (51.3mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 80.0mg, 93% yield.
1H NMR(500MHz,CDCl3)δ＝7.78(d,J＝7.9Hz,1H),7.36–7.32(m,2H),7.26–7.16(m,6H),7.09(dt,J＝7.4,1.0Hz,1H),6.97(t,J＝7.7Hz,1H),4.09(d,J＝2.1Hz,2H),1.99(s,3H),1.91(s,3H)ppm.13C NMR(126MHz,CDCl3) δ 143.3,142.1,138.3,137.0,136.8,136.3,136.3,129.9,129.3,128.9,128.4,128.2,127.1,127.1,124.1,101.4,37.3,21.2,19.8ppm hrms m/z (esi): calculated value C21H20IS[M+H]+431.0325, found 431.0341. ee values were determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.5mL/min,254nm, 99% ee); t is tr＝9.74min(S),tr＝11.63min(R).
The structural formula of the product is as follows:
example 6
Synthesis of Compound IIIf
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), 2-bromobenzyl (75.0mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 83.3mg, 82% yield.
1H NMR(500MHz,CDCl3)δ＝7.82(dd,J＝8.0,1.1Hz,1H),7.55(dd,J＝7.9,1.3Hz,1H),7.48(dd,J＝7.7,1.7Hz,1H),7.30–7.24(m,2H),7.22(td,J＝7.5,1.3Hz,1H),7.17–7.12(m,2H),7.10(td,J＝7.7,1.7Hz,1H),7.00(t,J＝7.7Hz,1H),4.22(s,2H),2.04(s,3H),1.95(s,3H)ppm.13C NMR(126MHz,CDCl3) 143.3,142.4,138.4,136.8,136.4,136.2,135.8,132.8,130.9,130.0,129.3,128.8,128.3,127.5,127.3,124.7,124.5,101.4,37.5,21.3,19.8ppm hrms m/z (esi): calculated value C21H19BrIS[M+H]+508.9430, found 508.9448.ee by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.4mL/min,254nm, 99% ee); t is tr＝10.19min(S),tr＝10.62min(R).
The structural formula of the product is as follows:
example 7
Synthesis of Compound IIIg
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), 1-bromomethylnaphthalene (66.3mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 78.7mg, 82% yield.
1H NMR(500MHz,CDCl3)δ＝8.10–8.04(m,1H),7.88–7.83(m,1H),7.79(d,J＝7.9Hz,1H),7.76(d,J＝8.2Hz,1H),7.56–7.52(m,1H),7.49(td,J＝6.9,6.4,3.6Hz,2H),7.37(dd,J＝8.2,7.1Hz,1H),7.34–7.28(m,2H),7.23(d,J＝7.5Hz,1H),7.19–7.15(m,1H),6.96(t,J＝7.7Hz,1H),4.61–4.53(m,2H),2.02(s,3H),1.97(s,3H)ppm.13C NMR(126MHz,CDCl3) δ 143.4,142.7,138.3,136.8,136.6,136.4,133.9,132.2,131.8,129.9,129.2,128.6,128.3,128.2,127.5,127.5,126.1,125.7,125.3,125.2,124.1,101.4,35.8,21.2,19.9ppm hrms m/z (esi): calculated value C25H21INaS[M+Na]+503.0301, found 503.0306.ee values determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.4mL/min,254nm, 99% ee); t is tr＝7.44min(S),tr＝8.05min(R).
The structural formula of the product is as follows:
example 8
Synthesis of Compound IIIh
Optically pure biaryl starting material Ia (91.4mg, 0.2mmol), 2-bromomethylnaphthalene (66.3mg, 0.3mmol), potassium hydroxide (22.4mg, 0.4mmol) were dissolved in 4mL of ethanol and the solution was stirred at room temperature for 3 h. Concentration, silica gel column chromatography, petroleum ether/ethyl acetate 100:1 elution, concentration afforded 79.7mg, 83% yield.
1H NMR(500MHz,CDCl3)δ＝7.86–7.74(m,5H),7.49(dd,J＝8.5,1.8Hz,1H),7.48–7.42(m,2H),7.29–7.26(m,1H),7.23(d,J＝4.9Hz,2H),7.11(td,J＝4.0,3.6,0.8Hz,1H),7.00(t,J＝7.7Hz,1H),4.28(d,J＝2.1Hz,2H),2.02(s,3H),1.94(s,3H)ppm.13C NMR(126MHz,CDCl3)δ＝143.3,142.1,138.3,136.8,136.3,136.1,134.5,133.3,132.6,130.0,129.3,128.2,128.2,127.7,127.6,127.5,127.1,126.1,125.8,124.1,101.4,37.4,21.3,19.8ppm. HRMS m/z (ESI): calculated value C25H21INaS[M+Na]+503.0301, found 503.0309.ee values determined by HPLC using a chiral IC column (n-hexane: isopropanol 99.5:0.5,0.4mL/min,254nm, 99% ee); t is tr＝4.79min(S),tr＝5.37min(R).
The structural formula of the product is as follows:
application examples
The compound synthesized by the invention is used as a chiral high-valence iodine catalyst in the asymmetric reaction:
m-chlorophenylacetone (33.7mg, 0.2mmol), chiral biaryl iodide (sample was the compound synthesized above, 0.02mmol), p-toluenesulfonic acid monohydrate (76.1mg, 0.4mmol), m-chloroperoxybenzoic acid (121.8mg, 0.6mmol, purity 85%) were dissolved in ethyl acetate (2ml) and reacted at 30 ℃ for 72 h. Concentrating, performing silica gel column chromatography, eluting with petroleum ether/ethyl acetate (10: 1), and concentrating to obtain product IV.
1H NMR(500MHz,CDCl3)δ7.83–7.77(m,2H),7.77–7.71(m,2H),7.56(ddd,J＝8.0,2.1,1.0Hz,1H),7.41(t,J＝7.9Hz,1H),7.32–7.25(m,2H),5.70(q,J＝6.9Hz,1H),2.44(s,3H),1.61(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3) δ 194.0,145.3,135.3,135.2,133.7,133.3,130.0,129.8,128.8,128.0,126.8,21.7,18.6.ee values were determined by HPLC using a chiral IC column (n-hexane: isopropanol 80:20,1.0mL/min,254 nm).
Claims (4)
1. A synthetic method of a biaryl axial chiral alkyl sulfide (III) is characterized by comprising the following steps:
uniformly mixing an optically pure biaryl axial chiral sulfur-containing heterocyclic compound (I), a compound (II), an alkaline substance and a solvent ethanol, reacting at room temperature for 2-4 h, and then carrying out post-treatment on a reaction solution to obtain a product biaryl axial chiral alkyl sulfide (III);
wherein the ratio of the amounts of the compound (I), the compound (II) and the alkaline substance is 1: 1-3: 1-3;
the reaction formula is as follows:
in the formulae (I), (II) and (III),
R1、R2each independently is: C5-C10 aryl, substituted C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl, unsaturated C2-C6 alkyl, nitro, trifluoromethyl, hydroxyl, ester group or halogen;
R3、R4each independently is: hydrogen, C5-C10 aryl, substituted C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl, unsaturated C2-C6 alkyl, nitro, ester group or halogen;
R5comprises the following steps: C5-C10 aryl, substituted C5-C10 aryl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C8 cyclic alkyl or unsaturated C2-C6 alkyl;
x is: oxygen or sulfur;
y is: chloro, bromo, iodo, methanesulfonyl or p-toluenesulfonyl;
n is: an integer of 0 to 4.
2. The method of synthesis of claim 1, wherein the basic material is sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide.
3. The synthetic method according to claim 1, wherein the volume usage of the solvent ethanol is 10 to 30mL/mmol based on the substance of the compound (I).
4. The synthesis method according to claim 1, wherein the reaction solution is post-treated by: after the reaction is finished, concentrating the reaction solution, and performing column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate is (100-5): 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent and drying to obtain the target product (III).
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| Cu-Catalyzed Enantioselective Atropisomer Synthesis via Thiolative Ring Opening of Five-Membered Cyclic Diaryliodoniums;Mengqing Hou et al.;《Org. Lett.》;20180907;第20卷;第5779-5783页 * |
| Reactions of (BenzothiazoI-2-ylthio)(trimethylsilyl)methane. A General Method for -Mercaptoalkylation by Alkylation and Alkylative Desilylation;Alan R.Katritzky et al.;《J. Org. Chem.》;19871231;第52卷(第5期);第844-849页 * |
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