CN113416149B - 一种氮杂环卡宾催化合成的联芳基类轴手性化合物及其制备方法 - Google Patents
一种氮杂环卡宾催化合成的联芳基类轴手性化合物及其制备方法 Download PDFInfo
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- CN113416149B CN113416149B CN202110887850.8A CN202110887850A CN113416149B CN 113416149 B CN113416149 B CN 113416149B CN 202110887850 A CN202110887850 A CN 202110887850A CN 113416149 B CN113416149 B CN 113416149B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 14
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 8
- 125000005841 biaryl group Chemical group 0.000 title claims abstract 4
- 238000002360 preparation method Methods 0.000 title claims description 112
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 title claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title claims description 4
- 238000000034 method Methods 0.000 claims abstract description 22
- -1 hydroxy, methoxy Chemical group 0.000 claims abstract description 21
- 125000005843 halogen group Chemical group 0.000 claims abstract description 18
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims abstract description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims abstract description 4
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract 4
- 125000001424 substituent group Chemical group 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 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 abstract description 14
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- 125000004093 cyano group Chemical group *C#N 0.000 description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000005347 biaryls Chemical group 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- GZWGTVZRRFPVAS-UHFFFAOYSA-N 1-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1N=C=O GZWGTVZRRFPVAS-UHFFFAOYSA-N 0.000 description 1
- FCEKLQPJGXIQRY-UHFFFAOYSA-N 1-isothiocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1N=C=S FCEKLQPJGXIQRY-UHFFFAOYSA-N 0.000 description 1
- LSRTWJCYIWGKCQ-UHFFFAOYSA-N 2-bromo-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1Br LSRTWJCYIWGKCQ-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000007296 Stetter synthesis reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical group 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
- C07C231/065—By hydration using metals or metallic ions as catalyst
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
- C07C273/1827—X being H
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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Abstract
Description
技术领域
本发明涉及一种氮杂环卡宾有机小分子催化合成联芳基类轴手性化合物的制备方法。
背景技术
氮杂环卡宾(NHC)有机催化在过去的二十年里得到了广泛的研究,在NHC催化活化的反应中,亚胺类化合物是一类常见的结构单元,提供了多种有效的反应模式。例如,Xue-Long Hou课题组在2008 年首次发现NHC催化剂活化苯甲醛亚胺形成aza-Breslow中间体,通过Ts基团的解离制备出多种取代的芳基腈。Akkattu T.Biju课题组在 2018年利用NHC催化剂活化亚胺形成aza-Breslow中间体,通过分子内的Michael受体环化生产2-(杂)芳基吲哚-3-乙酸衍生物,Akkattu T.Biju课题组在2018年利用NHC催化剂活化亚胺形成aza-Breslow 中间体与分子内的双键发生aza-Stetter反应合成了喹啉衍生物,2020 年,姚昌盛课题组利用NHC催化剂活化亚胺形成aza-Breslow中间体,进一步发生Ts基团的解离制备出多种取代的芳基腈。目前,利用NHC 有机小分子催化,通过动态动力学拆分实现轴手性苯腈类化合物的合成还没有报道。
发明内容
本发明要解决的技术问题是:设计合成出一类结构新颖、底物普适性好和高对映选择性的轴手性联芳基类化合物及其衍生物。
本发明的技术方案是:一种氮杂环卡宾催化合成的联芳基类轴手性化合物,所述的化合物结构式如式(1):其中, A环为苯环或萘环;B环为苯环或萘环;R2为羟基、甲氧基、三氟甲磺酸酯或二苯基膦;R4为氰基,氨甲基,甲酰胺或硫代甲酰胺;A 环为苯环时,R1为烷基、甲氧基或卤素原子;B环为苯环时,R3 为烷基、甲氧基或卤素原子;A环和B环为萘环时,R1和R3为氢。
所述A环的R1中取代基为3位卤原子、甲基、异丙基或甲氧基,或4位为甲基或甲氧基;或5位为甲基;或6位为甲基、甲氧基、乙基、异丙基或卤素原子。
所述B环的R3中的取代基为3位卤原子或甲基;或4位为甲基、卤素原子、甲氧基、硝基或苯基;或5位为甲基、甲氧基或卤素原子;或6位为甲基、甲氧基、乙基或卤素原子。
所述的化合物的制备方法,反应通式及过程如下:
所述的的合成路线如下:
本发明的有益效果:具有简单结构单元的反应物分子联芳基苯甲醛在氮杂环卡宾(NHC)的催化下,高效的制备了联芳基类轴手性化合物,并具有底物普适性好、优异的产率和高对映选择性;通过简单的转化,可以实现羟基到三氟甲磺酸酯、二苯基膦,氰基到伯胺、酰胺、硫代甲酰胺等一系列衍生物转化,且部分衍生物在不对称合成中可以用作催化剂或配体。
具体实施方式
以下介绍本发明的实施例,介绍38个制备实施例。
联芳基苯甲醛1的合成路线:
合成路线1:
步骤1.将S1、S2依次加入到乙醇溶液中,再加入催化量的吡啶。将反应混合物在80摄氏度下搅拌4小时,让混合物冷却到室温,然后在0摄氏度下再搅拌一小时,有白色固体析出,抽滤,用少量乙醇洗涤,旋干得到产物S3。
步骤2.将S3溶解在二氯甲烷溶液中,加入S4和催化剂S5。反应混合物回流12h,然后加入2,3-二氯-5,6-二氰-1,4-苯醌。4h后,将反应混合物冷却至室温,通过硅藻土过滤去除不溶性固体。滤液旋干,经柱层析分离(洗脱剂为石油醚和乙酸乙酯)可得到产物S6。
步骤3.在0摄氏度下,将S6溶解在四氢呋喃溶液中,缓慢加入氢化铝锂,转至室温搅拌,TCL跟踪监测,反应完后,加入盐酸中和(PH约为7),乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,过柱得到产物 S7。
步骤4.在0摄氏度下,将S7溶解在四氢呋喃溶液中,缓慢加入氯铬酸吡啶盐,在0摄氏度搅拌0.5~2.0h后,通过短硅胶柱过滤反应混合物以去除不溶性固体。滤液旋干,过柱得到产物1。
合成路线2:
步骤1.将2-溴-3-甲基苯甲酸S8溶于二氯甲烷中,DMF作为催化剂,在0 摄氏度下加入草酰氯。在0摄氏度下搅拌1h后转至室温搅拌3h。将此反应液逐滴加入到溶解有苯酚、催化量4-二甲氨基吡啶、三乙胺的二氯甲烷体系中,然后将混合物在室温下搅拌3小时。滤液旋干,过柱得到产物S9。
步骤2.将酯S9、醋酸钯、三苯基膦和无水醋酸钠溶解于N,N-二甲基乙酰胺中,在N2保护下加热至130摄氏度搅拌24小时。冷却至室温后加入饱和食盐水,乙酸乙酯萃取,无水硫酸钠干燥,旋干,过柱得到产物S10.
步骤3,步骤4同合成路线1所述。
制备实施例1
制备一种氮杂环卡宾催化合成轴手性类衍生物(3a-3ab)的合成路线:
制备实施方法和条件如下:
在氮气氛围的手套箱中,分别称取0.10mmol取代联芳基苯甲醛1、0.11 mmol磺酰胺2、0.02mmol(9.2mg)的氮杂环卡宾催化剂G,50mg 分子筛加入配有磁力搅拌子的4mL反应瓶中,随后加入1mL甲苯,0.10mmol(10.3 μL)二乙胺,搅拌反应至TLC监测联芳基苯甲醛消耗完毕后,湿法上样,通过柱层析分离(洗脱剂极性石油醚:乙酸乙酯=10:1),得到目标化合物3,称量后计算相应的产率,化合物通过熔点仪,旋光仪,核磁共振仪NMR,高分辨质谱仪HRMS和高效液相色谱仪HPLC予以表征。
A环取代基R1为6-甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-腈(3a):
=7.6Hz,1H),6.76(d,J=8.1Hz,1H),4.84(s,1H),2.11(s,3H),1.98(s,3H).
13C NMR(101MHz,CDCl3)δ192.9,153.0,139.4,138.9,137.9,136.5,134.8,129.6,128.8,125.6,122.6,122.5,113.2,20.2,19.2.
HRMS(ESI,m/z)calcd.for C15H13NOH+[M+H]+:224.1070,found:224.1073;
HPLC分析:98:2er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=32.9min,Rt(minor)=40.9min.
制备实施例2
A环取代基R1为4,6-二甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-4',6,6'-三甲基-[1,1'-联苯]-2-腈(3b):
13C NMR(101MHz,CDCl3)δ152.1,140.0,139.8,139.5,136.9,134.6,130.9,128.4,123.7,121.0,118.0,114.6,113.9,21.3,19.7,19.5.
HRMS(ESI,m/z)calcd.for C16H15NOH+[M+H]+:238.1226,found:238.1228.
HPLC分析:98:2er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=31.4min,Rt(minor)=40.0min.
制备实施例3
A环取代基R1为4,5,6-三甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-6'-羟基-2',3',4',6-三甲基-[1,1'-联苯]-2-腈(3c):
13C NMR(101MHz,CDCl3)δ149.6,140.9,139.5,138.2,135.1,134.5,130.8,128.2,127.8,121.6,118.1,114.7,114.7,20.9,19.8,16.9,15.3.
HRMS(ESI,m/z)calcd.for C17H17NOH+[M+H]+:252.1383,found:252.1387.
HPLC analysis:92:8er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=31.9min,Rt(minor)=38.6min.
制备实施例4
A环取代基R1为3,4,6-三甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-3',4',6,6'-三甲基-[1,1'-联苯]-2-腈(3d):
2.29(s,3H),2.16(s,3H),2.10(s,3H),1.91(s,3H).
13C NMR(101MHz,CDCl3)δ149.9,139.8,139.6,138.1,134.6,133.0,131.0,128.4,123.9,120.8,119.8,117.7,114.7,20.0,19.6,19.1,11.5.
HRMS(ESI,m/z)calcd.for C17H17NOH+[M+H]+:252.1383,found:252.1386.
UPLC analysis:96:4er(IB-U column,25℃,n-hexane/i-PrOH=96/4,0.3mL/min,λ=254nm),Rt(major)=9.4min,Rt(minor)=5.3min.
制备实施例5
A环取代基R1为4,6-二甲氧基、R2为羟基,B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-2'-羟基-4',6'-二甲氧基-6-甲基-[1,1'-联苯]-2-腈(3e):
1.4Hz,2H),3.80(s,3H),3.71(s,3H),2.13(s,3H).
13C NMR(101MHz,Acetone-d6)δ161.8,158.6,155.8,139.9,138.9,133.6,129.8,127.4,118.5,115.4,106.4,93.9,90.3,55.1,54.6,19.1.
HRMS(ESI,m/z)calcd.for C16H15NO3H+[M+H]+:270.1125,found:270.1127.
HPLC analysis:95:5er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=30.2min,Rt(minor)=28.3min.
制备实施例6
A环取代基R1为3-氯-4,6-二甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-3'-氯-6'-羟基-2',4',6-三甲基-[1,1'-联苯]-2-腈(3f):
(s,3H),2.10(s,3H),2.02(s,3H).
13C NMR(101MHz,CDCl3)δ150.4,139.4,139.4,138.0,135.1,134.8,131.0,128.7,127.1,122.8,117.7,115.7,114.5,21.1,19.7,17.7.
HRMS(ESI,m/z)calcd.for C16H14ClNOH+[M+H]+:272.0837,found:272.0845.
UPLC analysis:86:14er(IB-U column,25℃,n-hexane/i-PrOH=97/3,0.4mL/min,λ=254nm),Rt(major)=8.5min,Rt(minor)=6.5min.
制备实施例7
A环取代基R1为3,6-二甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-3',6,6'-三甲基-[1,1'-联苯]-2-腈(3g):
(d,J=7.7Hz,1H),4.39(s,1H),2.25(s,3H),2.09(s,3H),1.94(s,3H).
13C NMR(101MHz,CDCl3)δ150.4,139.9,139.5,134.7,134.4,131.1,128.6,123.4,122.2,121.3,117.8,114.5,19.6,19.4,15.8.
HRMS(ESI,m/z)calcd.for C16H15NOH+[M+H]+:238.1226,found:238.1227.
UPLC analysis:95:5er(IB-U column,25℃,n-hexane/i-PrOH=95/5,0.5mL/min,λ=254nm),Rt(major)=9.2min,Rt(minor)=4.2min.
制备实施例8
A环取代基R1为3-甲氧基,R2为羟基;R2为羟基;B环取代基R3为6-甲基, R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-3'-甲氧基-6,6'-二甲基-[1,1'-联苯]-2-腈(3h):
5.62(s,1H),3.91(s,3H),2.10(s,3H),1.94(s,3H).
13C NMR(101MHz,CDCl3)δ144.8,142.8,140.9,138.8,134.4,130.6,129.0,128.1,123.7,121.2,118.4,113.9,110.7,56.2,19.8,19.1.
HRMS(ESI,m/z)calcd.for C16H15NO2H+[M+H]+:254.1176,found:254.1177;
HPLC analysis:90:10er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min,λ=254nm),Rt(major)=40.5min,Rt(minor)=49.9min.
制备实施例9
A环取代基R1为3-异丙基、6-甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-3'-异丙基-6,6'-二甲基-[1,1'-联苯]-2-腈(3i):
6.91(d,J=7.9Hz,1H),4.34(s,1H),3.17–3.27(m,1H),2.12 (s,3H),1.96(s,3H),1.31–1.26(m,6H).
13C NMR(101MHz,CDCl3)δ149.3,139.7,139.7,134.8,133.9,132.1,131.2,128.7,126.4,123.4,122.4,117.6,114.8,27.1,22.7,22.5,19.6,19.3.
HRMS(ESI,m/z)calcd.for C18H19NOH+[M+H]+:266.1540,found:266.1541.
UPLC analysis:96:4er(IB-U column,25℃,n-hexane/i-PrOH=97/3,0.3mL/min,λ=254nm),Rt(major)=6.8min,Rt(minor)=4.4min.
制备实施例10
A环取代基R1为3-氯-6-甲基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-3'-氯-2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-腈(3j):
(d,J=8.3Hz,1H),5.51(s,1H),2.09(s,3H),1.97(s,3H).
13C NMR(101MHz,CDCl3)δ148.3,140.0,138.6,136.8,134.5,130.6,128.9,128.3,125.1,123.0,118.0,117.7,113.6,19.7,19.3.
HRMS(ESI,m/z)calcd.for C15H12ClNOH+[M+H]+:258.0680,found:258.0681.
HPLC analysis:86:14er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=40.2min,Rt(minor)=27.9min.
制备实施例11
A环取代基R1为6-甲氧基,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-2'-羟基-6'-甲氧基-6-甲基-[1,1'-联苯]-2-腈(3k):
=8.3Hz,1H),6.69–6.62(m,2H),3.71(s,3H),2.12(s,3H).
13CNMR(101MHz,Acetone-d6)δ157.9,155.2,139.4,138.9,133.7,130.1,129.9,127.6,118.4,114.8,113.6,108.7,102.6,55.2,19.1.
HRMS(ESI,m/z)calcd.for C15H13NO2H+[M+H]+:240.1020,found:240.1020.
UPLC analysis:93:7er(IB column,25℃,n-hexane/i-PrOH=95/5,0.5mL/min,λ=254nm),Rt(major)=4.7min,Rt(minor)=10.8min.
制备实施例12
A环取代基R1为6-氯,R2为羟基;B环取代基R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-2'-氯-6'-羟基-6-甲基-[1,1'-联苯]-2-腈(3l):
7.13(d,J=0.9Hz,1H),6.84(dd,J=8.2,0.9Hz,1H),5.12(s,1H),2.15(s,3H).
13C NMR(101MHz,CDCl3)δ154.0,139.5,138.0,134.7,134.0,130.7,130.7,128.9,123.5,121.8,117.8,114.5,114.1,19.6.
HRMS(ESI,m/z)calcd.for C14H10ClNOH+[M+H]+:244.0524,found:244.0524.
UPLC analysis:95:5er(IB column,25℃,n-hexane/i-PrOH=95/5,0.5mL/min,λ=254nm),Rt(major)=3.4min,Rt(minor)=4.7min.
制备实施例13
A环取代基R1为4,6-二甲基,R2为羟基;B环取代基R3为5,6-二甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-4',5,6,6'-三甲基-[1,1'-联苯]-2-腈(3m):
13C NMR(101MHz,CDCl3)δ152.4,143.1,139.7,139.6,138.0,137.0,130.5,129.9,123.5,121.6,118.4,113.9,111.9,21.3,21.2,19.6,16.2.
HRMS(ESI,m/z)calcd.for C17H17NOH+[M+H]+:252.1382,found:252.1388.
HPLC analysis:97:3er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min,λ=254nm),Rt(major)=37.3min,Rt(minor)=27.9min.
制备实施例14
A环取代基R1为4,6-二甲基,R2为羟基;B环取代基R3为4,6-二甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-4,4',6,6'-三甲基-[1,1'-联苯]-2-腈(3n):
白色固体,95%收率,23.8mg;熔点:76-77℃.
136.7,135.6,131.3,123.6,120.8,118.1,114.4,113.8,21.3,20.9,19.6,19.5.
HRMS(ESI,m/z)calcd.for C17H17NOH+[M+H]+:252.1382,found:252.1387.
HPLC analysis:97:3er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=27.6min,Rt(minor)=46.2min.
制备实施例15
A环取代基R1为4,6-二甲基,R2为羟基;B环取代基R3为4-氯-6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-4-氯-2'-羟基-4',6,6'-三甲基-[1,1'-联苯]-2-腈(3o):
13C NMR(101MHz,CDCl3)δ152.1,141.3,140.1,139.0,137.1, 134.5,133.9,130.2,123.8,120.0,116.8,115.8,114.0,21.3,19.7,19.4.
HRMS(ESI,m/z)calcd.for C16H14ClNOH+[M+H]+:272.0837,found:272.0840.
HPLC analysis:94:6er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=21.1min,Rt(minor)=23.0min.
制备实施例16
A环取代基R1为4,6-二甲基,R2为羟基;B环取代基R3为6-甲氧基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-2'-羟基-6-甲氧基-4',6'-二甲基-[1,1'-联苯]-2-腈(3p):
1H),4.96(s,1H),3.76(s,3H),2.28(s,3H),1.99(s,3H).
13C NMR(101MHz,CDCl3)δ157.7,152.8,139.8,137.9,129.8,129.6,125.0,123.5,118.3,117.8,115.6,115.6,114.1,56.1,21.4,19.6.
HRMS(ESI,m/z)calcd.for C16H15NO2H+[M+H]+:254.1175,found:254.1174.
UPLC analysis:98:2er(IB-U column,25℃,n-hexane/i-PrOH=70/30,0.8mL/min,λ=254nm),Rt(major)=8.9min,Rt(minor)=6.7min.
制备实施例19
A环取代基R1为6-甲基,R2为羟基;B环取代基R3为6-乙基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-6-乙基-2'-羟基-6'-甲基-[1,1'-联苯]-2-腈(3q):
Hz,1H),6.79(d,J=8.1Hz,1H),4.83(s,1H),2.44(q,J=7.6Hz,2H),2.01(s,3H),1.10(t,J=7.6Hz,3H).
13C NMR(101MHz,CDCl3)δ152.6,145.1,139.3,137.5,133.1,130.9,129.7,128.7,123.7,122.6,117.9,114.4,113.3,26.2,19.7,14.4.
HRMS(ESI,m/z)calcd.for C16H15NOH+[M+H]+:238.1226,found:238.1227.
HPLC analysis:93:7er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=27.3min,Rt(minor)=34.0min.
制备实施例20
A环取代基R1为6-甲氧基,R2为羟基;B环取代基R3为6-乙基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-6-ethyl-2'-羟基-6'-甲氧基-[1,1'-联苯]-2-腈(3r):
(m,2H),3.71(s,3H),2.46(q,J=7.6Hz,2H),1.03(t,J=7.6Hz,3H).
13C NMR(101MHz,Acetone-d6)δ158.1,155.4,145.2,138.4,132.3,130.1,129.9,127.9,118.3,114.9,113.5,108.6,102.5,55.2,26.3,14.0.
HRMS(ESI,m/z)calcd.for C16H15NO2H+[M+H]+:254.1175,found:254.1174.
HPLC analysis:93:7er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min,λ=254nm),Rt(major)=36.9min,Rt(minor)=38.8min.
制备实施例17
A环取代基R1为6-甲基,R2为羟基;B环取代基R3为4,6-二甲基,R4为氰基;
制备实施方法和条件同制备实施例1;
(S)-2'-羟基-4,6,6'-三甲基-[1,1'-联苯]-2-腈(3s):
(s,1H),2.41(s,3H),2.07(s,3H),1.99(s,3H).
13C NMR(101MHz,CDCl3)δ152.5,139.0,138.7,137.5,136.5,135.7,131.4,129.6,123.7,122.6,117.9,114.1,113.1,20.9,19.6,19.6.
HRMS(ESI,m/z)calcd.for C16H15NOH+[M+H]+:238.1226,found:238.1228.
HPLC analysis:97:3er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min,λ=254nm),Rt(major)=56.2min,Rt(minor)=60.9min.
制备实施例18
A环取代基R1为6-甲氧基,R2为羟基;B环取代基R3为4,6-二甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-2'-羟基-6'-甲氧基-4,6-二甲基-[1,1'-联苯]-2-腈(3t):
3.71(s,3H),2.36(s,3H),2.07(s,3H).
13C NMR(101MHz,Acetone-d6)δ158.1,155.4,139.1,137.5,135.9,134.6,130.1,129.9,118.5,114.6,113.5,108.6,102.5,55.2,19.8,19.0.
HRMS(ESI,m/z)calcd.for C16H15NO2H+[M+H]+:254.1175,found:254.1178.
HPLC analysis:93:7er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min,λ=254nm),Rt(major)=39.4min,Rt(minor)=42.8min.
制备实施例21
A环取代基R1为4,6-二甲基,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-1-(2-羟基-4,6-二甲基苯基)-2-萘甲腈(3u):
(s,1H),6.70(s,1H),4.45(d,J=4.1Hz,1H),2.38(s,3H),1.90(s, 3H).
13C NMR(101MHz,CDCl3)δ151.3,141.5,135.7,135.2,131.9,131.7,129.4,129.3,128.7,128.4,127.2,126.7,122.4,122.3,121.7,118.3,111.8,19.7,16.0.
HRMS(ESI,m/z)calcd.for C19H15NOH+[M+H]+:274.1226,found:274.1233.
UPLC analysis:93:7er(IB-U column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=13.4min,Rt(minor)=10.3min.
制备实施例22
A环取代基R1为4,6-二甲氧基,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(R)-1-(2-羟基-4,6-二甲基苯基)-2-萘甲腈(3v):
7.50(m,1H),6.34(dd,J=5.2,2.2Hz,2H),3.85(s,3H),3.65(s, 3H).
13C NMR(101MHz,Acetone-d6)δ162.3,159.3,156.5,140.4,135.0,132.7,128.3,128.2,128.2,127.1,127.1,126.7,118.7,112.3,105.0,94.0,90.5,55.2,54.7.
HRMS(ESI,m/z)calcd.for C19H15NO3H+[M+H]+:306.1125,found:306.1127.
HPLC analysis:95:5er(IB column,25℃,n-hexane/i-PrOH=90/10,0.5mL/min,λ=254nm),Rt(major)=42.4min,Rt(minor)=40.1min.
制备实施例23
A环取代基R1为3,4,6-三甲基,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-1-(2-羟基-3,4,6-三甲基苯基)-2-萘甲腈(3w):
4.24(s,1H),2.34(s,3H),2.19(s,3H),1.87(s,3H).
13C NMR(101MHz,CDCl3)δ150.8,141.5,138.8,135.1,134.2,131.9,129.2,129.2,128.6,128.2,127.1,126.6,124.2,120.1,119.8,118.2,111.9,20.3,19.4,11.7.
HRMS(ESI,m/z)calcd.for C20H17NOH+[M+H]+:288.1383,found:288.1382.
HPLC analysis:96:4er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=62.0min,Rt(minor)=57.0min.
制备实施例24
A环取代基R1为3-异丙基-6-甲基,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-1-(2-羟基-3-异丙基-6-甲基苯基)-2-萘甲腈(3x):
1H),3.19–3.30(m,1H),1.92(s,3H),1.34(d,J=1.3Hz,3H),1.32(d,J=1.3Hz,3H).
13C NMR(101MHz,CDCl3)δ150.1,141.2,135.1,135.0,132.3,131.7,129.3,129.2,128.6,128.3,127.1,126.8,126.5,122.5,122.2,118.0,111.9,27.1,22.7,22.7,19.5.
HRMS(ESI,m/z)calcd.for C21H19NOH+[M+H]+:302.1540,found:302.1538.
HPLC analysis:90:10er(AD-H column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=34.6min,Rt(minor)=53.3min.
制备实施例25
A环取代基R1为3,6-二甲基,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-1-(2-羟基-3,6-二甲基苯基)-2-萘甲腈(3y):
7.19(d,J=7.7Hz,1H),6.90(d,J=7.7Hz,1H),4.34(d,J=2.4Hz,1H),2.29(s,3H),1.89(s,3H).
13C NMR(101MHz,CDCl3)δ151.3,141.5,135.7,135.2,131.9,131.7,129.4,129.3,128.7,128.4,127.2,126.7,122.4,122.3,121.7,118.3,111.8,19.7,16.0.
HRMS(ESI,m/z)calcd.for C19H15NOH+[M+H]+:274.1226,found:274.1232.
HPLC analysis:86:14er(IB column,25℃,n-hexane/i-PrOH=96/4,0.4mL/min,λ=254nm),Rt(major)=31.6min,Rt(minor)=28.0min.
制备实施例26
A环取代基R1为6-甲基,R2为甲氧基;B环R3为6-甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-甲氧基-6,6'-二甲基-[1,1'-联苯]-2-腈(3z):
3H).
13C NMR(101MHz,CDCl3)δ156.6,141.8,138.5,137.3,134.1,130.3,129.5,127.6,126.1,122.7,118.4,113.8,108.5,55.8,19.7,19.5.
制备实施例27
A环为萘环,R2为羟基;B环R3为4,6-二甲基,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-1'-(2'-羟基萘基)-4,6-二甲基苯甲腈(3aa):
Hz,1H),7.08–7.01(m,1H),5.23(d,J=25.7Hz,1H),2.43(s,3H), 1.99(s,3H).
13C NMR(101MHz,CDCl3)δ150.6,140.2,139.0,135.9,135.3,132.8,131.6,130.7,129.1,128.4,127.1,123.6,123.5,118.1,117.7,116.6,115.0,21.0,19.7.
HRMS(ESI,m/z)calcd.for C19H15NOH+[M+H]+:274.1226,found:274.1231.
HPLC分析:er 70:30((IB column,25℃,Hexane/iPrOH=96/4,flow rate=0.4mL/min,λ=254nm),Rt(major)=39.4min,Rt(minor)=45.9min.
制备实施例28
A环为萘环,R2为羟基;B环为萘环,R4为氰基;制备实施方法和条件同制备实施例1;
(S)-2'-羟基-[1,1'-联萘]-2-腈(3ab):
16.8,8.2Hz,2H),7.66–7.71(m,1H),7.49–7.42(m,2H),7.39–7.30(m,2H),7.26(td,J=7.6,6.8,1.3Hz,1H),6.88(d,J=8.4Hz,1H).
13C NMR(101MHz,Acetone)δ153.0,141.5,135.2,134.0,132.6,130.8,129.1,128.8,128.7,128.6,128.3,127.7,127.0,127.0,126.9,123.7,123.2,118.3,118.2,115.7,112.4.
HRMS(ESI,m/z)calcd.for C21H13NOH+[M+H]+:296.0997,found:296.1004.
HPLC分析:54:46er(AD-H column,25℃,n-hexane/i-PrOH=95/5,0.4mL/ min,λ=254nm),Rt(minor)=53.5min,Rt(major)=57.1min.
制备实施例29
制备实施方法和条件如下:
在Schlenk管中加入3a,吡啶和二氯甲烷,冷却至0℃,缓慢加入三氟甲烷磺酸酐。将反应混合物转至室温,搅拌2h,然后过柱,用二氯甲烷作为洗脱剂,得到化合物5。
(S)-2'-氰基-6,6'-二甲基-[1,1'-联苯]-2-三氟甲磺酸酯(5):
Hz,1H),7.29(d,J=8.1Hz,1H),2.11(d,J=4.2Hz,6H).
13C NMR(101MHz,CDCl3)δ146.9,139.7,138.8,137.4,134.7,130.8,130.7,130.4,130.3,129.1,119.1,118.3(q,J=321.2Hz),117.5,114.0,19.7,19.6.
19F NMR(377MHz,CDCl3)δ-74.6.
HRMS(ESI,m/z)calcd.for C16H12F3NO3SNa+[M+Na]+:378.0382,found 378.0385.
HPLC分析:97:3er(IE column,25℃,n-hexane/i-PrOH=98/2,0.4mL/min,λ=254nm),Rt(major)=25.4min,Rt(minor)=24.1min.
制备实施例30
制备实施方法和条件如下:
氮气保护下将化合物5、二苯基膦氧、醋酸钯、dppb和二异丙基乙胺加入到二甲基亚砜中并在100℃搅拌3h。然后将反应混合物冷却至室温后浓缩,加入乙酸乙酯,用水洗涤,无水硫酸钠干燥,浓缩后将残渣直接置于Schlenk管中,置换氮气,加入甲苯和二异丙基乙胺,再加入三氯硅烷,然后将反应加热至100℃搅拌2h。冷却至室温后,加入饱和碳酸氢钠水溶液淬灭反应,沉淀物用硅藻土过滤去除,用乙酸乙酯萃取,无水硫酸镁干燥。浓缩后,过柱(20:1石油醚/乙酸乙酯)纯化,用二氯甲烷/石油醚重结晶后,化合物6的光学纯度提高(>99:1er值)。 (S)-2'-(二苯基膦)-6,6'-二甲基-[1,1'-联苯]-2-腈(6):
=7.6Hz,1H),7.35–7.26(m,9H),7.18–7.22(m,4H),7.03–7.06(m,1H),1.97(s,3H),1.81(s,3H).
13C NMR(101MHz,CDCl3)δ143.8(d,J=7.3Hz),142.9(d,J=31.4Hz),138.4(d, J=2.2Hz),137.4(d,J=11.3Hz),136.4(dd,J=11.2,7.8Hz),136.2(d,J=5.9Hz), 134.3–133.5(m),134.2,132.0,131.2,130.3,(d,J=12.0Hz),128.7(d,J=12.0Hz),128.5(d,J=9.4Hz),128.5–128.3(m),127.9,118.1,114.2(d,J=3.0Hz),19.9(d,J =2.7Hz),19.8(d,J=3.7Hz).
31P NMR(162MHz,CDCl3)δ-13.94.
HRMS(ESI,m/z)calcd.for C27H22NPH+[M+H]+:392.1563,found 392.1562.
HPLC分析:97:3er(ID column,25℃,n-hexane/i-PrOH=90/10,0.4mL/min,λ=254nm),Rt(major)=14.0min,Rt(minor)=18.5min.
制备实施例31
制备实施方法和条件如下:
将化合物6溶解于四氢呋喃中,于0℃下加入硼烷-四氢呋喃,加毕将体系升至室温并搅拌1h。然后将反应体系逐渐加热至70℃,搅拌回流30min后,冷却至0℃,缓慢加入甲醇(5.0mL)淬灭反应。将得到的溶液在室温下搅拌20分钟,浓缩后,加入四氢呋喃,加入1M稀盐酸,将混合物在室温下搅拌5分钟,然后加热回流2分钟,冷却至室温后,加入饱和碳酸氢钠水溶液。旋蒸去除有机溶剂后,用二氯甲烷萃取,无水硫酸钠干燥。用三乙胺/甲醇/二氯甲烷(1:10:100) 过柱得到化合物7。
(S)-(2'-(二苯基膦酰基)-6,6'-二甲基-[1,1'-联苯]-2-基)甲胺(7):
14.8Hz,1H),3.2(d,J=14.9Hz,1H),2.9(s,2H),1.9(s,3H),1.6(s,3H).
13C NMR(101MHz,CDCl3)δ144.8(d,J=32.2Hz),138.8(d,J=1.6Hz),138.2(d, J=7.9Hz),137.0(d,J=9.5Hz),136.7,136.5,136.5,134.1(d,J=7.2Hz),133.9(d,J=7.0Hz),131.8,131.0,128.7,128.6(d,J=1.9Hz),128.6–128.1(m),127.6, 124.4,43.5(d,J=2.8Hz),20.0(d,J=2.7Hz),20.0(d,J=3.3Hz).
31P NMR(162MHz,CDCl3)δ-14.41.
HRMS(ESI,m/z)calcd.for C27H26NPH+[M+H]+:396.1876,found 396.18730.
制备实施例32
制备实施方法和条件如下:
将化合物3a,乙醛肟,醋酸钯和三苯基膦溶解在EtOH/H2O(v/v=4/1)中,70℃搅拌3h,然后浓缩,过柱得到化合物8。
(S)-2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-甲酰胺(8):
7.8Hz,1H),6.82(s,1H),6.80(s,1H),6.47(d,J=30.0Hz,2H),1.95(s,3H),1.86(s, 3H).
13C NMR(101MHz,Acetone)δ172.2,155.1,138.6,138.6,138.4,135.7,132.2,129.5,128.3,128.1,126.4,122.8,114.8,20.2,20.1.
HRMS(ESI,m/z)calcd.for C15H15NO2Na+[M+Na]+:264.0995,found:264.0999.
UPLC分析:96:4er(IC-U column,25℃,n-hexane/i-PrOH=90/10,0.5mL/ min,λ=254nm),Rt(major)=8.0min,Rt(minor)=7.0min.
制备实施例33
制备实施方法和条件如下:
将五硫化二膦溶于乙醇中搅拌1h后加入化合物3a,反应体系在70℃搅拌24h 后浓缩,过柱得到化合物9。
(S)-2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-硫代酰胺(9):
(dt,J=7.7,1.0Hz,1H),6.76(d,J=8.1Hz,1H),5.35(s,1H),1.95(d,J=4.6Hz, 6H).
13C NMR(101MHz,CDCl3)δ205.1,152.2,142.6,138.1,137.7,131.8,130.7,129.1,128.3,126.7,125.8,123.3,113.2,19.9,19.8.
HRMS(ESI,m/z)calcd.for C15H15NOSH+[M+H]+:258.0947,found:258.0939.
UPLC分析:99:1er(IA-U column,25℃,n-hexane/i-PrOH=95/5,0.4mL/min, λ=254nm),Rt(major)=4.9min,Rt(minor)=5.8min.
制备实施例34
制备实施方法和条件同制备实施例28;
(S)-2'-(氨甲基)-6,6'-二甲基-[1,1'-联苯]-2-酚(10):
1H),4.18(s,3H),3.57(d,J=12.6Hz,1H),3.41(d,J=12.4Hz,1H),1.94(s,3H),1.84(s,3H).
13C NMR(101MHz,CDCl3)δ154.2,139.8,138.0,137.1,136.6,129.7,128.5,128.0,127.9,126.1,122.1,115.8,45.0,19.9,19.8.
HRMS(ESI,m/z)calcd.for C15H17NONa+[M+Na]+:250.1202,found:250.1199.
制备实施例35
制备实施方法和条件如下:
将化合物10溶于四氢呋喃中,加入3,5-双(三氟甲基苯基)异硫氰酸酯,室温下搅拌30分钟,然后浓缩,过柱(6:1石油醚/乙酸乙酯)得到化合物11。
(S)-1-(3,5-双三氟甲基苯基)-3-((2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-基)甲基)硫脲 (11):
7.35–7.26(m,2H),7.10(t,J=7.9Hz,1H),6.82(d,J=7.6Hz,1H),6.61(d,J=8.1Hz,1H),6.41(s,1H),4.70(s,2H),4.17(dd,J=14.6,4.7Hz,1H),1.96(s,3H),1.86 (s,3H).
13C NMR(101MHz,CDCl3)δ180.3,151.7,138.8,138.2,137.3,135.6,134.2,132.7(q,J=32.3Hz),130.5,129.2,128.9,127.6,125.2,124.5,123.0,122.8(q,J=272.9Hz),119.5,113.0,47.5,19.6,19.6.
19F NMR(377MHz,CDCl3)δ-63.01.
HRMS(ESI,m/z)calcd.for C24H20F6N2OSNa+[M+Na]+:521.1093,found:521.1091.
HPLC分析:98:2er(IB column,25℃,n-hexane/i-PrOH=90/10,0.5mL/min,λ=254nm),Rt(major)=37.2min,Rt(minor)=23.5min.
制备实施例36
制备实施方法和条件如下:
将化合物10溶于四氢呋喃中,加入3,5-双(三氟甲基苯基)异氰酸酯,室温下搅拌30分钟,然后浓缩,过柱(6:1石油醚/乙酸乙酯)得到化合物12。
(S)-1-(3,5-双(三氟甲基)苯基)-3-((2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-基)甲基)硫脲 (12):
1H),7.32(s,1H),7.30–7.22(m,3H),7.11(t,J=7.8Hz,1H),6.85(d,J=7.5Hz,1H),6.72(d,J=8.1Hz,1H),5.55(t,J=5.7Hz,1H),5.44(s,1H),4.08(dd,J=15.0,6.4Hz,1H),3.91(dd,J=14.9,4.9Hz,1H),1.93(s,3H),1.85(s,3H).
13C NMR(101MHz,CDCl3)δ155.0,152.0,140.2,138.1,137.3,137.1,134.0,132.0(q,J=33.2Hz),130.0,129.0,128.7,126.2,125.5,123.1(q,J=273.0Hz),122.9,118.8,116.0,113.2,42.8,19.6,19.5.
19F NMR(377MHz,CDCl3)δ-63.32.
HRMS(ESI,m/z)calcd.for C24H20F6N2O2Na+[M+Na]+:505.1321,found:505.1325.
HPLC分析98:2er(IB column,25℃,n-hexane/i-PrOH=85/15,0.5mL/min,λ=254nm),Rt(major)=32.0min,Rt(minor)=17.3min.
制备实施例37
制备实施方法和条件如下:
将化合物10溶于乙腈中,加入1,1-二甲氧基-N,N-二甲基乙胺,在在室温下搅拌 1小时后,浓缩,三乙胺/甲醇/二氯甲烷(1:10:100)过柱得到化合物13。
(S,E)-N'-((2'-羟基-6,6'-二甲基-[1,1'-联苯]-2-基)甲基)-N,N-二甲基乙酰亚胺(13):
2H),6.78(d,J=7.5Hz,1H),4.32(d,J=9.7Hz,1H),4.14(d,J=14.3Hz,1H),3.04(s,6H),1.93(s,3H),1.85(s,3H),1.67(s,3H).
13C NMR(101MHz,CDCl3)δ162.5,154.6,137.8,137.3,136.7,133.5,130.1,128.8,127.8,127.7,125.2,121.5,113.9,47.8,41.5,40.6,19.7,19.6,14.3.
HRMS(ESI,m/z)calcd.for C19H24N2OH+[M+H]+:297.1961,found:297.1970。
制备实施例38
制备实施方法和条件如下:
将化合物13溶于醇中,加入氢氧化钠水溶液,在在室温下搅拌4小时后,浓缩,过柱(石油醚/乙酸乙酯=10:1)得到化合物14。
=5.5Hz,1H),4.19(dd,J=14.4,6.7Hz,1H),3.84(dd,J=14.4,4.4Hz,1H),1.96(s, 3H),1.87(s,3H),1.84(s,3H).
13C NMR(101MHz,CDCl3)δ170.2,152.8,137.9,137.2,137.0,135.0,129.8,128.8,128.4,126.8,125.7,122.3,113.4,42.5,23.0,19.7,19.7.
HRMS(ESI,m/z)calcd.for C17H19NO2Na+[M+Na]+:292.1308,found:292.1309.
HPLC分析:98:2er(AD-H column,25℃,n-hexane/i-PrOH=90/10,1.0mL/ min,λ=254nm),Rt(major)=7.0min,Rt(minor)=8.3min.
Claims (4)
2.根据权利要求1所述的制备方法,其特征在于:所述A环的R1中取代基为3位卤原子、甲基、异丙基或甲氧基,或4位为甲基或甲氧基;或5位为甲基;或6位为甲基、甲氧基、乙基、异丙基或卤素原子。
3.根据权利要求1所述的制备方法,其特征在于:所述B环的R3中的取代基为3位卤原子或甲基;或4位为甲基、卤素原子或甲氧基;或5位为甲基、甲氧基或卤素原子;或6位为甲基、甲氧基、乙基或卤素原子。
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