CN113620851A - Chiral beta-diester selenoethers and Michael addition preparation method thereof - Google Patents
Chiral beta-diester selenoethers and Michael addition preparation method thereof Download PDFInfo
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- CN113620851A CN113620851A CN202110961773.6A CN202110961773A CN113620851A CN 113620851 A CN113620851 A CN 113620851A CN 202110961773 A CN202110961773 A CN 202110961773A CN 113620851 A CN113620851 A CN 113620851A
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- Prior art keywords
- alkyl
- diester
- radical
- group
- chiral
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006845 Michael addition reaction Methods 0.000 title claims abstract description 21
- -1 C2-C20Alkenyl radical Chemical class 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 239000003054 catalyst Substances 0.000 claims description 36
- 239000003153 chemical reaction reagent Substances 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 150000003254 radicals Chemical class 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000000654 additive Substances 0.000 claims description 14
- 230000000996 additive effect Effects 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000002808 molecular sieve Substances 0.000 claims description 12
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 150000003958 selenols Chemical class 0.000 claims description 11
- 229940126062 Compound A Drugs 0.000 claims description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 7
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 150000002240 furans Chemical class 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 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 4
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004430 oxygen atom Chemical group 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 125000006735 (C1-C20) heteroalkyl group Chemical group 0.000 claims description 3
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 3
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 3
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 2
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910052796 boron Inorganic materials 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
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims 1
- 235000019796 monopotassium phosphate Nutrition 0.000 claims 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 9
- 239000008204 material by function Substances 0.000 abstract description 6
- 125000000524 functional group Chemical group 0.000 abstract description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 125000005842 heteroatom Chemical group 0.000 description 21
- 125000000304 alkynyl group Chemical group 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 239000000376 reactant Substances 0.000 description 13
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 239000011669 selenium Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000003197 catalytic effect Effects 0.000 description 8
- 125000004404 heteroalkyl group Chemical group 0.000 description 8
- 229910052711 selenium Inorganic materials 0.000 description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 5
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 230000001588 bifunctional effect Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 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
- SMAHKNUQZLXYLW-UHFFFAOYSA-N CC(C)(C)C[SeH] Chemical compound CC(C)(C)C[SeH] SMAHKNUQZLXYLW-UHFFFAOYSA-N 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000003957 organoselenium compounds Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical class OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003342 selenium Chemical class 0.000 description 1
- 229940065287 selenium compound Drugs 0.000 description 1
- 150000003343 selenium compounds Chemical class 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the technical field of organic compound synthesis, and particularly provides a chiral beta-diester selenide compound and a Michael addition preparation method thereof. The molecular structural general formula of the chiral beta-diester selenide compound is shown as an instruction formula I: the chiral beta-diester selenide compound has high functional group and structural diversity, so that the compound can provide diversified selections for the chiral beta-diester selenide compound in the synthesis of drug intermediates and the application of functional materials, and is particularly applied to the synthesis of malonate products and the preparation of functional materials.
Description
Technical Field
The application belongs to the technical field of organic compound synthesis, and particularly relates to a chiral beta-diester selenide compound and a Michael addition preparation method thereof.
Background
Selenium is a trace element, and chemists have increasingly paid attention to organic selenium compounds and have significant influence on the fields of medicinal chemistry, material chemistry, chemical biology, biochemistry and the like. While chiral organoselenium compounds are synthesized mainly from chiral substrates or controlled by chiral catalysts, methods controlled by chiral substrates have been significantly developed, but the strategy of asymmetric catalytic synthesis is less concerned.
Currently, asymmetric selenium Michael additions mainly utilize electrophiles or nucleophiles of selenium. The reported selenium Michael reaction is the Michael addition of arylselenols to ketenes using chiral cinchona-based catalysts, but the ee value is only 43% at the maximum. These methods have a number of disadvantages, for example: 1) the asymmetric reaction of aryl selenium is designed only, and the asymmetric catalytic reaction of alkyl selenium is not realized; 2) asymmetric Michael addition has not yet achieved synthesis with high stereoselectivity; 3) the alkenyl ester compound has not been reported to be asymmetric selenium Michael. Therefore, there is a need for a novel synthesis method that overcomes the drawbacks of the prior art, particularly those described above.
Disclosure of Invention
The application aims to provide chiral beta-diester selenoethers and a preparation method of Michael addition thereof, and aims to solve the problems of limited substrate and low enantioselectivity in the existing asymmetric selenium Michael addition.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides a chiral beta-diester selenide compound, wherein the molecular structural general formula of the chiral beta-diester selenide compound is shown as formula I:
wherein R is1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups.
In a second aspect, the present application provides a method for preparing the above chiral β -diester selenoethers by Michael addition, comprising the following steps:
providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound.
The chiral beta-diester selenide compound provided by the application can provide raw materials or reaction intermediates for synthesis of drug intermediates and preparation of functional materials; and the chiral beta-diester selenide compounds have high functional group, so that diversified choices can be provided for the beta-diester selenide compounds in the synthesis of drug intermediates and the application of functional materials.
The Michael addition method of the chiral beta-diester selenide compounds provided by the application is a novel asymmetric C-Se bond construction method, and has the following advantages:
firstly, the application adopts an organic micromolecule asymmetric catalytic system to realize Michael addition of the chiral beta-diester selenide compounds.
Secondly, according to the Michael addition method, on one hand, a simple selenol compound reagent is used as a nucleophilic reagent to attack an alkene diester compound, so that a target product precursor with high enantioselectivity and a wide range is efficiently and greenly prepared, and a chiral beta-diester selenide compound with potential application is obtained; on the other hand, the reactant selects simple and easily available selenol and commercial diester alkene as the reactant, the raw material is very easy to obtain, and the reactant can be directly used for preparation production without additional modification protection before reaction, so that the operation steps are simplified, the reaction route is shortened, in addition, the forward reaction rate is high, and the production efficiency is obviously improved.
Thirdly, in the Michael addition process of the application, the Michael addition process of the chiral beta-diester selenide compounds is a conjugate addition reaction, so that the atom utilization rate and the reaction efficiency of reactants are high, the generation yield of reaction products is favorably improved, in addition, the selenol compound A and the alkene diester compound B are prepared by one-step reaction in a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, the preparation method has simple process and low requirement on reaction conditions, the reaction process is safe and controllable, and the operation in the preparation production process is simplified.
Fourthly, the method provided by the application obviously reduces the production cost of preparing the beta-diester selenide compounds, and also greatly expands the designability and application prospect of the compounds. The addition product obtained by the method has high functional group, so that the addition product is more diversified in the synthesis of a drug intermediate and the application of a functional material, can be widely used for the synthesis of the drug intermediate and the preparation of the functional material, can effectively reduce the economic cost for the preparation of the drug intermediate and the functional material, and provides the environmental friendliness.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
The compounds and derivatives thereof referred to in the examples of the present invention are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, Ohio) naming system. Accordingly, the groups of compounds specifically referred to in the examples of the present invention are illustrated and described as follows:
with respect to "hydrocarbon group", the minimum and maximum values of the carbon atom content in a hydrocarbon group are indicated by a prefix, e.g., the prefix (C)a-Cb) Alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C)1-C6) Alkyl refers to alkyl groups containing one to six carbon atoms.
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (C)a-Cb) Alkoxy means any straight or branched, monovalent, saturated aliphatic chain in which an alkyl group containing "a" to "b" carbon atoms is bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" means a straight or branched, monovalent, saturated aliphatic chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar groups.
"alkenyl" refers to straight or branched chain hydrocarbons having one or more double bonds, including but not limited to, groups such as ethenyl, propenyl, and the like.
"Heteroalkenyl" means a straight or branched chain hydrocarbon with one or more double bonds attached to at least one heteroatom, including but not limited to, for example, vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched chain hydrocarbon with one or more triple bonds, including but not limited to, for example, ethynyl, propynyl, and the like.
"Heteroalkynyl" means a straight or branched chain hydrocarbon with one or more triple bonds attached to at least one heteroatom, including but not limited to, groups such as ethynyl, propynyl, and the like.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like.
"cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group. Cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocycloalkyl" means a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocycloalkyl groups include, but are not limited to, groups such as azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, and the like.
"cycloalkenyl" refers to an unsaturated, monocyclic or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cyclic ethenyl, cyclopropenyl, or other similar groups.
"Heterocycloalkenyl" means an unsaturated, monocyclic or polycyclic alkenyl radical having one or more double bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated, monocyclic or polycyclic alkynyl group having one or more triple bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cycloalkynyl, cyclopropynyl, or the like.
"Heterocycloalkynyl" means an unsaturated, monocyclic or polycyclic alkynyl radical having one or more triple bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
The first aspect of the embodiments of the present application provides a chiral β -diester selenide compound, where the molecular structural general formula of the chiral β -diester selenide compound is shown in formula I:
in the general formula I, R1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl group、C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups;
when R is1、R2And R3Are identical or different C1-C20Alkyl, in some embodiments, C1-C20The alkyl group may be (C)1-C10) Alkyl, (C)1-C5) Alkyl, (C)1-C4) Alkyl, (C)1-C3) Alkyl, (C)1-C2) Alkyl groups, and the like. In some embodiments, (C)1-C20) The alkyl group may be specifically a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, etc.
When R is1、R2And R3Are identical or different (C)1-C20) When it is heteroalkyl, in one embodiment, (C)1-C20) The heteroalkyl group may be (C)1-C10) Heteroalkyl group, (C)1-C5) Heteroalkyl group, (C)1-C4) Heteroalkyl group, (C)1-C3) Heteroalkyl group, (C)1-C2) Heteroalkyl groups and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkyl, in one embodiment, (C)3-C20) The cycloalkyl group may be (C)3-C10) Cycloalkyl radicals、(C3-C5) Cycloalkyl group, (C)3-C4) Cycloalkyl groups, and the like. In one embodiment, (C)3-C20) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When it is a heterocycloalkyl group, in one embodiment, (C)3-C20) The heterocycloalkyl group may be (C)3-C10) Heterocycloalkyl group, (C)3-C10) Heterocycloalkyl group, (C)3-C5) Heterocycloalkyl group, (C)3-C4) Heterocycloalkyl, and the like. In one embodiment, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)2-C20) Alkenyl, in one embodiment, (C)2-C20) The alkenyl group may be (C)3-C10) Alkenyl, (C)3-C5) Alkenyl, (C)3-C4) Alkenyl, (C)2-C3) Alkenyl groups, and the like. In some embodiments, (C)2-C20) The alkenyl group may be ethenyl, propenyl, butenyl, pentenyl, etc.
When R is1、R2And R3Are identical or different (C)2-C20) (iii) heteroalkenyl, in one embodiment, (C)2-C20) The heteroalkenyl group can be (C)2-C10) Heteroalkenyl, (C)3-C10) Heteroalkenyl, (C)3-C5) Heteroalkenyl, (C)3-C4) Heteroalkenyl, (C)2-C3) Heteroalkenyl and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkenyl in one embodiment, (C)3-C20) Cycloalkenyl can be (C)3-C10) Cycloalkenyl group, (C)3-C5) Cycloalkenyl group, (C)3-C4) Cycloalkenyl groups, and the like. In some casesIn the examples, (C)3-C20) Cycloalkenyl can be cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When heterocycloalkenyl, in one embodiment, (C)3-C20) The heterocycloalkenyl group may be (C)3-C10) Heterocycloalkenyl, (C)3-C5) Heterocycloalkenyl, (C)3-C4) Heterocycloalkenyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R3And R3Are identical or different (C)2-C20) Alkynyl, in one embodiment, (C)2-C20) Alkynyl may be (C)2-C10) Alkynyl, (C)3-C10) Alkynyl, (C)3-C5) Alkynyl, (C)3-C4) Alkynyl, (C)2-C3) Alkynyl and the like. In some embodiments, (C)2-C20) The alkynyl group may be an ethynyl group, propynyl group, butynyl group, pentynyl group or the like.
When R is1、R2And R3Are identical or different (C)2-C20) When heteroalkynyl is present, (C) is, in one embodiment2-C20) The heteroalkynyl can be (C)2-C10) Heteroalkynyl, (C)3-C10) Heteroalkynyl, (C)3-C5) Heteroalkynyl, (C)3-C4) Heteroalkynyl, (C)2-C3) Heteroalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkynyl, in one embodiment, (C)3-C20) The cycloalkynyl group can be (C)3-C10) Cycloalkynyl, (C)3-C5) Cycloalkynyl, (C)3-C4) Cycloalkynyl, and the like. In some embodiments, (C)2-C20) The cycloalkynyl group can be cyclopropynyl, cyclobutynyl,Cyclopentynyl, and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When heterocycloalkynyl, in one embodiment, (C)3-C20) The heterocycloalkynyl can be (C)3-C10) Heterocycloalkynyl, (C)3-C5) Heterocycloalkynyl, (C)3-C4) Heterocycloalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)1-C20) In the case of alkoxy, in one embodiment, (C)1-C20) The alkoxy group may be (C)1-C10) Alkoxy group, (C)1-C8) Alkoxy group, (C)1-C6) Alkoxy group, (C)1-C4) Alkoxy group, (C)1-C3) Alkoxy group, (C)1-C2) An alkoxy group. In some embodiments, (C)1-C20) Alkoxy groups may be, but are not limited to, methyloxy, ethyloxy, propyloxy, and the like.
When R is1、R2And R3When the aryl groups are the same or different, the aryl groups may be, but are not limited to, monocyclic aryl groups, polycyclic aryl groups, and fused ring aryl groups. In one embodiment, the aryl group is a monocyclic aryl group. In some embodiments, aryl is phenyl.
When R is1、R2And R3When the same or different substituted aryl groups are present, the substituted aryl groups may be, but are not limited to, phenyl groups substituted singly or multiply in the ortho, meta, or para positions. Substituents include, but are not limited to, alkyl, substituted alkyl, halogen, alkoxyamino, nitro, -NR7R8、-NR7-CO-NR8、-OCONR7、-PR7R8、-SOR7、-SO2-R7、-SiR7R8R9、-BR7R8Wherein R is7、R8、R9Which may be the same or different is as R above1、R3The groups shown. Wherein is substitutedWhen the radical is alkyl, alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, isobutyl; when the substituent is a substituted alkyl group, the water absorbing additive is a substituted alkyl group such as, but not limited to, trifluoromethyl, trichloromethyl, trifluoroethyl, trichloroethyl; when the substituent is halogen, halogen such as, but not limited to, fluorine, chlorine, bromine, iodine; when the substituent is an alkoxy group, the water absorbing additive alkoxy group is, for example, but not limited to, a methyloxy group, an ethyloxy group, a propyloxy group. In one embodiment, the substituted aryl group may also be cyano (C)1-C10) Alkyl radical (C)3-C8) Aryl, substituted (C)3-C8) And (4) an aryl group.
When R is1、R2And R3When the same or different heteroaryl groups are present, in one embodiment, the heteroaryl group can be (C)3-C8) Heteroaryl, furan, thiophene.
When R is1、R2And R3In the case of identical or different substituted heteroaryl groups, in one embodiment the substituted heteroaryl groups may be substituted (C)3-C8) Heteroaryl, alkoxy substituted furan, (C)3-C8) Heteroaryl substituted furans, aliphatic chain substituted thiophenes.
When R is1、R2And R3When the same or different aryloxy groups are present, in one embodiment, the aryloxy group can be phenoxy, naphthoxy, anthracenoxy, phenanthroxy.
When R is1、R2And R3Are identical or different aryl radicals (C)1-C20) When it is an alkyl group, in one embodiment, the aryl group (C)1-C20) The alkyl group may be aryl (C)1-C10) Alkyl, phenyl (C)1-C10) Alkyl, phenyl (C)1-C5) Alkyl, phenyl (C)1-C4) Alkyl, phenyl (C)1-C3) Alkyl, phenyl (C)1-C2) Alkyl groups, and the like. In some embodiments, aryl (C)1-C20) The alkyl group can be phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylIsoamyl and phenyl neopentyl.
When R is1、R2And R3Are identical or different heteroaryl (C)1-C20) When alkyl, in one embodiment, the heteroaryl (C)1-C20) The alkyl group may be heteroaryl (C)1-C10) Alkyl, heteroaryl (C)1-C10) Alkyl, heteroaryl (C)1-C5) Alkyl, heteroaryl (C)1-C4) Alkyl, heteroaryl (C)1-C3) Alkyl, heteroaryl (C)1-C2) Alkyl groups, and the like. Wherein the heteroaryl group may be (C)3-C8) Heteroaryl, furan, pyridine, and the like.
When R is1、R2And R3Are identical or different (C)2-C20) Alkenyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkenyl (C)1-C20) The alkyl group may be (C)2-C10) Alkenyl (C)1-C10)、(C2-C5) Alkenyl (C)1-C3). In certain embodiments, the (C)2-C20) Alkenyl (C)1-C20) The alkyl group may be 2-butenyl, 2-pentenyl, 3-hexenyl, 3-heptenyl, etc.
When R is1、R2And R3Are identical or different (C)2-C20) Alkynyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkynyl (C)1-C20) The alkyl group may be (C)2-C10) Alkynyl (C)1-C10) Alkyl, (C)2-C5) Alkynyl (C)1-C3) An alkyl group. In certain embodiments, the (C)2-C20) Alkynyl (C)1-C20) The alkyl group may be 2-butynyl, 2-pentynyl, 3-hexynyl, 3-heptynyl, etc.
When R is1、R2And R3Are identical or different cyano groups (C)1-C20) Alkyl, in one embodiment, the cyano (C)1-C20) The alkyl group may be cyano (C)1-C10) Alkyl, cyano (C)1-C5) Alkyl, cyano (C)1-C4) Alkyl, cyano (C)1-C3) Alkyl, cyano (C)1-C2) Alkyl groups, and the like. In certain embodiments, cyano (C)1-C20) The alkyl group may be cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, or the like.
When R is1、R2And R3Are identical or different C1-C20Alkyloxycarbonyl (C)1-C20) When it is alkyl, in one embodiment, the C1-C20Alkyloxycarbonyl (C)1-C20) The alkyl group may be (C)1-C10) Alkyloxycarbonyl (C)1-C10) Alkyl, (C)1-C5) Alkyloxycarbonyl (C)1-C5) Alkyl, (C)1-C4) Alkyloxycarbonyl (C)1-C4) Alkyl, (C)1-C3) Alkyloxycarbonyl (C)1-C3) Alkyl, (C)1-C2) Alkyloxycarbonyl (C)1-C2) Alkyl groups, and the like. In some embodiments, the alkyloxycarbonylalkyl group can be an ethoxycarbonylethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylmethyl group, propoxycarbonylpropyl group, propoxycarbonylethyl group, propoxycarbonylmethyl group, and the like.
In some embodiments, R1、R2And R3Are identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C3-C10Cycloalkyl radical, C3-C10Heterocycloalkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C3-C10Cycloalkenyl radical, C3-C10Heterocycloalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C10Cycloalkynyl group, C3-C10Heterocycloalkynyl, C1-C10Alkoxy radical, C1-C10Alkyloxycarbonyl (C)1-C10) Alkyl radical, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Alkyl, cyano (C)1-C10) Alkyl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl groups.
In some embodiments, R1、R2And R3Is C1-C5Alkyl radical, C1-C5Alkyloxycarbonyl (C)1-C5) Alkyl, phenyl (C)1-C3) Alkyl radical, C2-C5Alkenyl (C)1-C3) Alkyl radical, C2-C5Alkynyl (C)1-C3) Alkyl, cyano (C)1-C3) Alkyl, halogen-substituted phenyl, alkoxy-substituted furan, alkoxy-substituted pyridine, C3-C8Heteroaryl-substituted phenyl, C3-C8Heteroaryl substituted furans and C3-C8Any one of heteroaryl substituted pyridines.
Further, the chiral beta-diester selenoethers comprise at least one of the following structural formulas I1-I3:
the chiral beta-diester selenide compounds provided by the embodiment of the application have structural diversity and can be widely applied to synthesis of drug intermediates, particularly malonate products and preparation of functional materials. The chiral beta-diester selenide compound has high functional group, so that diversified choices can be provided for the application of the chiral selenide in the synthesis of drug intermediates and functional materials.
The chiral beta-diester selenide compounds provided by the embodiment of the application can be prepared by the following method.
The second aspect of the embodiments of the present application provides a method for preparing a chiral β -diester selenide compound by Michael addition, which includes the following steps:
s01, providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
s02, adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound shown in the formula I.
Specifically, in step S01, R in the molecular structural formula of selenol compound a is1The group represented by the formula and the R in the molecular structure general formula I of the chiral beta-diester selenide compound1The groups represented are the same. R in the molecular structural formula of diester compound B2、R3The group represented by the formula and R in the structural general formula I of the chiral beta-carbon-based selenide compound2、R3The groups represented are the same. For economy of disclosure, further description is omitted here.
The selenol compound a and the alkene diester compound B in step S01 may be prepared by themselves in accordance with a conventional preparation method, or may be directly obtained commercially.
The reactant raw materials provided by the embodiment of the application are very easy to obtain, and the reactant before reaction does not need to be additionally modified and can be directly used for preparation production, so that the operation steps are simplified, and the reaction route is shortened; the production cost is obviously reduced.
In step S02, it is known from the structural formula of the reactant alkene diester compound B that the reactant selenol compound a acts as a nucleophile and attacks the alkene diester substrate, so that the two reactants undergo a conjugate addition reaction. Therefore, the atom utilization rate of reactants is effectively improved, the limitation of a substrate can be widened, and the target product precursor with high enantioselectivity and extremely wide range is efficiently and greenly prepared, so that the chiral beta-diester selenide compound with potential application value is obtained through simple reduction reaction.
The conjugate addition reaction formula of the selenol compound a and the alkene diester compound B in the step S02 in the reaction environment and system in the step S02 is as follows:
in the chemical reaction formula, the nitrogen heterocyclic carbene catalyst, the alkali reagent and the water absorption additive act synergistically, so that the catalytic system is low in toxicity, the atom utilization rate and the reaction efficiency are improved, and byproducts are few; meanwhile, the reaction process is safe and controllable, and the operation in the preparation production process is simplified. The N-heterocyclic carbene catalyst can provide better non-covalent bond interaction, so that the enantiomeric excess (ee) value of a product is improved in the catalytic reaction process; the base reagent is used to react with the azacyclocarbene catalyst to deprotonate the azacyclocarbene reagent to form an activated protic base catalyst. The contents of the three components are in a certain range under a certain proportion condition, so that the reaction has high catalytic efficiency, and a target product with nearly single absolute configuration is obtained.
In order to make the synergistic catalytic system exert more effective catalytic action, in one embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is (0.1-20): (0.1-20). Under the condition, under the synergistic action of the N-heterocyclic carbene catalyst and the alkali reagent, the reaction has high catalytic efficiency, and the ee value of a reaction product is favorably improved. Preferably, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is (0.2-20):2 (1-10), and in this case, the target product with nearly single absolute configuration is favorably obtained. In another embodiment, the molar ratio of the azacyclocarbene catalyst to the alkali reagent is 1 (1-9). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-8). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-7). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-6). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-5). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-4). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-3). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-2). In one embodiment, the molar ratio of azacyclocarbene catalyst to base reagent is 1: 1.
In one embodiment, the mole ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the selenol compound A is (0.1-20): (0.2-40). In this case, the reaction has high catalytic efficiency, which is beneficial to improving the ee value of the reaction product. In some embodiments, the addition amount of the N-heterocyclic carbene catalyst and the alkali reagent in the reaction system is controlled to be the molar ratio of the N-heterocyclic carbene catalyst to the selenol compound A (0.2-20) to 2 (1-10).
In some embodiments, the azacyclo-carbene catalyst is at least one of a triazole azacyclo-carbene or a bifunctional azacyclo-carbene catalyst. In specific experiments, the bifunctional N-heterocyclic carbene catalyst can catalyze the reaction to be carried out more efficiently, but different carbene catalysts can cause products to have different enantioselectivities. In one embodiment, the azacyclo-carbene catalyst is selected from nitrogen-containing heterocyclic compounds represented by the following structural formula C and/or structural formula D:
C：
D：
in the structural general formulas C and D, X is identical or different boron tetrafluoride anions or chloride ions, and Y in the structural general formula D is an oxygen atom or a sulfur atom; r4、R5And R6Are identical or different aryl radicals (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
Further, the alkali agent is at least one selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, bistrimethylsilyl lithium, bistrimethylsilyl sodium, bistrimethylsilyl potassium, diisopropylamino lithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide and sodium ethylmercaptide.
In the reaction process of step S02 in the embodiment of the present application, the presence of water molecules easily disturbs the highly ordered transition state intermediate through hydrogen bond interaction, so that the embodiment of the present application introduces a water absorption additive into the reaction system to remove water in the reaction system, thereby effectively improving the enantioselectivity of the target product; meanwhile, the water absorption additive can ensure that the reaction system is in an anhydrous state, and under the condition, the alkali reagent cannot be quenched during reaction. In one embodiment, the water absorbing additive is selected from at least one of the following: anhydrous sodium sulfate, anhydrous magnesium sulfate, preactivated 13X molecular sieve,
Molecular sieve,
Molecular sieves and
and (3) a molecular sieve. Wherein, the preactivated 13 × molecular sieve is the molecular sieve obtained by heating and dehydrating the 13 × molecular sieve. The water absorbing additive is mainly used for controlling the anhydrous requirement of the reaction system, so the water absorbing additive can be used according to the reaction time and the solvent of the specific reaction systemProperties, etc., such as sufficient addition to achieve hydration free reaction system. In one embodiment, the ratio of the water absorbing additive enumerated above to the solvent for the reactant is controlled to 100 mg/mL.
In conclusion, in the preparation process of the chiral beta-diester selenide compound, the nitrogen heterocyclic carbene, the alkali reagent and the water absorbing reagent have synergistic effect, so that the catalytic system has low toxicity, high atom utilization rate and production efficiency, safe and controllable reaction process, and simplified operation in the preparation production process. Meanwhile, in a reaction system containing the N-heterocyclic carbene, the alkali reagent and the water absorbing reagent, the toxicity of the reaction residues is reduced to the minimum, the pollution to the environment in the production process is reduced, and the steps and the operation for removing the residues after the reaction are simplified. In addition, the proportion and the addition amount of the azacarbene catalyst, the alkali reagent and the reactant are flexibly adjusted, so that the high atom utilization rate and the production efficiency are further improved, and the production of byproducts is reduced.
The reaction temperature range applicable to the reaction system in the embodiment of the application is-100 ℃ to 25 ℃. In order to further improve the reaction efficiency and the enantioselectivity of the reaction product, in one embodiment, the reaction temperature of the reaction system is-100 ℃ to-40 ℃. In another embodiment, the reaction temperature of the reaction system is from-40 ℃ to-20 ℃. In another embodiment, the reaction temperature of the reaction system is-20 ℃ to 0 ℃. In another embodiment, the reaction temperature of the reaction system is 0 ℃ to 10 ℃. In another embodiment, the reaction temperature of the reaction system is 10 ℃ to 25 ℃. The reaction time in the environment of the temperature of each preferred reaction should be such that the above reactants are sufficiently reacted, for example, the reaction time may be 6 to 48 hours, or longer.
In the above reaction system, a certain amount of solvent is optionally added. Such solvents include, but are not limited to, diethyl ether, tetrahydrofuran, dichloromethane, toluene. In one embodiment, the solvent is added in a molar ratio of solvent to catalyst such that (1000- > 1000000): 1.
the chiral beta-diester selenide compounds provided by the embodiment of the application or the chiral beta-diester selenide compounds prepared by the Michael addition method have high functional group property, and can be widely applied to the research fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicines.
The following description will be given with reference to specific examples.
Example 1
This example provides (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) malonic acid diethyl ester and a preparation method thereof. The structural formula of the ((R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate is shown as the following molecular structural formula I1:
the preparation method comprises the following steps:
triazole carbene-thiourea bifunctional catalyst (0.01mmol, 0.1 equivalent (equiv.)), 13X molecular sieve (100mg) and n-hexylselenol nucleophile (0.2mmol, 2.0 equiv.)) were dissolved in 1.2mL of the mixed solvent of the pretreated diethyl ether, sealed with a rubber stopper, and then gas was replaced under argon atmosphere (3 times), bis (trimethylsilyl) aminolithium (LiHMDS) (1mol/L, tetrahydrofuran/ethylbenzene solution, 10 μ L, 0.10 equiv.)) was slowly added, and gas was replaced again under argon atmosphere (3 times). The tube was sealed with a sealing film and then stirred at-90 ℃ for 1 hour. Diethyl (E) -2- (4-methoxystyryl) malonate (0.10mmol, 1.0equiv.) was prepared as a solution of diethyl ether (0.6mL), and slowly injected using an injection pump (3 hours injection time), after which the mixture was reacted at-90 ℃ for 24 hours. After complete consumption of chalcone, the mixture was directly purified by column chromatography on silica gel (ethyl acetate and n-hexane as eluent) to give the desired product, and the enantioselectivity of the product was determined by chiral HPLC to give the desired product I1 in 95% yield and 90% ee.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),4.53(d,J＝11.7Hz,1H),4.25(qd,J＝7.1,3.5Hz,2H),4.04-3.87(m,3H),3.79(s,3H),2.58-2.26(m,2H),1.57-1.44(m,2H),1.32(t,J＝7.1Hz,3H),1.30-1.17(m,6H),1.02(t,J＝7.1Hz,3H),0.87(t,J＝7.0Hz,3H).13C NMR(101MHz,CD2Cl2)δ167.43,166.85,158.85,132.64,129.22,113.70,61.94,61.58,59.13,55.30,40.15,31.37,30.20,29.66,25.12,22.61,13.99,13.90,13.70.HRMS(ESI-TOF)[M+Na]calculated for[C21H32O5SeNa]+467.1307,observed 467.1308.Specific Rotation[α]D 25＝-70.6(c＝1.0in CH2Cl2) HPLC (Chiralpak-AD-H column, ethanol/hexane ═ 2.5/97.5,1.0mL/min): t (minor) 18.088min, t (major) 12.825min.
Example 2
This example provides (R) -2- (2- (4-methoxyphenyl) -2- (neopentyl seleno) ethyl) malonic acid diethyl ester and a preparation method thereof. The structural formula of the (R) -2- (2- (4-methoxyphenyl) -2- (neopentyl seleno) ethyl) diethyl malonate is shown as the following molecular structural formula I2:
the preparation method refers to the preparation method of (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate in example 1, and is different from the preparation method of (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate by adopting neopentyl selenol (0.2mmol) instead of n-hexylselenol. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain the target product, colorless liquid, the yield is 96 percent, and the ee value is 95 percent.
The product I2 prepared was subjected to characterization data analysis, the result of which was1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.6Hz,2H),6.83(d,J＝8.6Hz,2H),4.45(d,J＝11.7Hz,1H),4.30-4.17(m,2H),4.03-3.87(m,3H),3.79(s,3H),2.43(s,2H),1.33(t,J＝7.1Hz,3H),1.01(t,J＝7.1Hz,3H),0.90(s,9H).13C NMR(101MHz,CD2Cl2)δ167.40,166.81,158.84,132.66,129.40,113.64,61.94,61.57,59.37,55.30,41.16,41.05,31.94,29.18,14.00,13.69..HRMS(ESI-TOF)[M+Na]calculated for[C20H30O5SeNa]+453.1151,observed 453.1152.Specific Rotation[α]D 25＝-81.3(c＝1.0in CH2Cl2) HPLC (Chiralpak-IC-H column, ethanol/hexane ═ 1/99,1.0mL/min): t (minor) -10.685 min, t (major) -8.931 min.
Example 3
This example provides diethyl 2- ((R) -2- (4-methoxyphenyl) -2- (((S) -2-methylbutyl) seleno) ethyl) malonate and a method for preparing the same. The structural formula of diethyl 2- ((R) -2- (4-methoxyphenyl) -2- (((S) -2-methylbutyl) seleno) ethyl) malonate is shown as the following molecular structural formula I3:
the preparation method is as follows (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate preparation method in example 1, except that (S) -2-methylbutane-1-selenol (0.2mmol) is adopted to replace cyclopentylselenol. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain a target product, namely a colorless liquid, the yield is 96 percent, and the de value is 90 percent.
The product I3 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),4.50(d,J＝11.7Hz,1H),4.25(qd,J＝7.1,4.0Hz,2H),4.04-3.88(m,3H),3.79(s,3H),2.46(dd,J＝11.8,6.0Hz,1H),2.33(dd,J＝11.8,7.2Hz,1H),1.50-1.43(m,1H),1.35-1.28(m,4H),1.18-1.10(m,1H),1.02(t,J＝7.1Hz,3H),0.89-0.78(m,6H).13C NMR(101MHz,CD2Cl2)δ167.43,166.84,158.85,132.67,129.28,113.69,61.93,61.57,59.22,55.30,40.55,35.42,32.97,29.40,19.46,13.99,13.69,11.19.HRMS(ESI-TOF)[M+Na]calculated for[C20H30O5SeNa]+453.1151,observed 451.1149.Specific Rotation[α]D 25＝-69.0(c＝1.0in CH2Cl2) HPLC (Chiralpak-IC-H column, ethanol/hexane ═ 2.5/97.5,1.0mL/min): t (minor) 21.237min, t (major) 13.610min.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A chiral beta-diester selenide compound is characterized in that the molecular structural general formula of the chiral beta-diester selenide compound is shown as formula I:
wherein R is1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups.
2. The chiral β -diester selenoethers as claimed in claim 1 wherein R is1、R2And R3Are identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C3-C10Cycloalkyl radical, C3-C10Heterocycloalkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C3-C10Cycloalkenyl radical, C3-C10Heterocycloalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C10Cycloalkynyl group, C3-C10Heterocycloalkynyl, C1-C10Alkoxy radical, C1-C10Alkyloxycarbonyl (C)1-C10) Alkyl radical, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Alkyl, cyano (C)1-C10) Alkyl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl groups.
3. The chiral β -diester selenoethers as claimed in claim 2 wherein R is1、R2And R3Is C1-C5Alkyl radical, C1-C5Alkyloxycarbonyl (C)1-C5) Alkyl, phenyl (C)1-C3) Alkyl radical, C2-C5Alkenyl (C)1-C3) Alkyl radical, C2-C5Alkynyl (C)1-C3) Alkyl, cyano (C)1-C3) Alkyl, halogen-substituted phenyl, alkoxy-substituted furan, alkoxy-substituted pyridine, C3-C8Heteroaryl-substituted phenyl, C3-C8Heteroaryl substituted furans and C3-C8Any one of heteroaryl substituted pyridines.
4. The chiral β -diester selenoethers according to any one of claims 1 to 3, wherein the chiral β -diester selenoethers comprise at least one of the following structural formulae I1 to I3:
5. a method for the preparation of a Michael addition of chiral β -diester selenoethers as claimed in any one of claims 1 to 4, comprising the steps of:
providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound.
6. The method for preparing the chiral β -diselenide compound by Michael addition according to claim 5, wherein the molar ratio of the N-heterocyclic carbene catalyst to the base reagent is (0.1-20) to (0.1-20).
7. The method for preparing the chiral β -diester selenoethers according to claim 6 by Michael addition, wherein the molar ratio of the N-heterocyclic carbene catalyst, the base reagent and the selenol compound A is (0.1-20): (1-100).
8. The method for preparing the Michael addition of the chiral β -diester selenoethers according to claim 5, wherein the azacyclo-carbene catalyst is selected from nitrogen-containing heterocyclic compounds represented by the following structural formula C and/or structural formula D:
C：
D：
wherein X is identical or different boron tetrafluoride anions or chloride ions, and Y is an oxygen atom or a sulfur atom; r4、R5And R6Are identical or different aryl radicals (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
9. The method of claim 5, wherein the base reagent is at least one selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, bistrimethylaminolithium, bistrimethylaminosodium, bistrimethylaminopotassium, diisopropylaminolithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, and sodium ethylmercaptide.
10. The method of claim 5, wherein the water-absorbing additive is selected from the group consisting of anhydrous sodium sulfate, anhydrous magnesium sulfate, pre-activated 13x molecular sieve, and a mixture thereof,
Molecular sieve,
Molecular sieves and
at least one of molecular sieves.
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