CN115028624B - 一种喹喔啉骨架nn噁唑啉类配体及其合成方法和应用 - Google Patents
一种喹喔啉骨架nn噁唑啉类配体及其合成方法和应用 Download PDFInfo
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- CN115028624B CN115028624B CN202210571962.7A CN202210571962A CN115028624B CN 115028624 B CN115028624 B CN 115028624B CN 202210571962 A CN202210571962 A CN 202210571962A CN 115028624 B CN115028624 B CN 115028624B
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- 239000003446 ligand Substances 0.000 title claims abstract description 64
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims abstract description 26
- UPUZGXILYFKSGE-UHFFFAOYSA-N quinoxaline-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CN=C21 UPUZGXILYFKSGE-UHFFFAOYSA-N 0.000 claims abstract description 16
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims abstract description 14
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- 239000012298 atmosphere Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 9
- 239000004305 biphenyl Substances 0.000 claims description 7
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 7
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 4
- 238000009987 spinning Methods 0.000 claims description 3
- 150000005623 oxindoles Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 6
- TTXGKCVKGXHPRI-UHFFFAOYSA-N 4,5-dibromobenzene-1,2-diamine Chemical compound NC1=CC(Br)=C(Br)C=C1N TTXGKCVKGXHPRI-UHFFFAOYSA-N 0.000 abstract description 4
- XSZYBMMYQCYIPC-UHFFFAOYSA-N 4,5-dimethyl-1,2-phenylenediamine Chemical compound CC1=CC(N)=C(N)C=C1C XSZYBMMYQCYIPC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 26
- -1 acyclic olefins Chemical class 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 20
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 18
- 150000001414 amino alcohols Chemical class 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000011630 iodine Substances 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- OMEMIVABNROXRE-UHFFFAOYSA-N CC=1C=C2N=CC(=NC2=CC=1C)C=O Chemical compound CC=1C=C2N=CC(=NC2=CC=1C)C=O OMEMIVABNROXRE-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- OIFADUQNTPUCKK-KRWDZBQOSA-N (4r)-4-phenyl-2-quinolin-2-yl-4,5-dihydro-1,3-oxazole Chemical compound C1([C@H]2N=C(OC2)C=2N=C3C=CC=CC3=CC=2)=CC=CC=C1 OIFADUQNTPUCKK-KRWDZBQOSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZSOLLSAKMTZPAJ-UHFFFAOYSA-N 2,6,7-trimethylquinoxaline Chemical compound C1=C(C)C(C)=CC2=NC(C)=CN=C21 ZSOLLSAKMTZPAJ-UHFFFAOYSA-N 0.000 description 4
- ITFVFBUYVYYGLJ-UHFFFAOYSA-N 6,7-diphenylquinoxaline Chemical group c1ccc(cc1)-c1cc2nccnc2cc1-c1ccccc1 ITFVFBUYVYYGLJ-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
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 4
- JOAAHJHQXOCSAW-UHFFFAOYSA-N 6,7-dimethylquinoxaline Chemical group C1=CN=C2C=C(C)C(C)=CC2=N1 JOAAHJHQXOCSAW-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000004986 phenylenediamines Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 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 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
- RSNQVABHABAKEZ-UHFFFAOYSA-N 2,3-diphenylquinoxaline Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2N=C1C1=CC=CC=C1 RSNQVABHABAKEZ-UHFFFAOYSA-N 0.000 description 1
- YOCRKHKJFCWTHG-UHFFFAOYSA-N 2-[6-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC(C=2OCCN=2)=N1 YOCRKHKJFCWTHG-UHFFFAOYSA-N 0.000 description 1
- 238000003540 Heck arylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940120731 pyruvaldehyde Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- ULVLJDHWMPPRLN-IBGZPJMESA-N tert-butyl (3S)-3-fluoro-3-(4-fluorophenyl)-2-oxoindole-1-carboxylate Chemical compound C1([C@@]2(F)C(=O)N(C3=CC=CC=C32)C(=O)OC(C)(C)C)=CC=C(F)C=C1 ULVLJDHWMPPRLN-IBGZPJMESA-N 0.000 description 1
- ROJCTGFXGJZWFA-FQEVSTJZSA-N tert-butyl (3S)-3-fluoro-3-(4-fluorophenyl)-5-methoxy-2-oxoindole-1-carboxylate Chemical compound C1([C@@]2(F)C(=O)N(C(=O)OC(C)(C)C)C3=CC=C(C=C32)OC)=CC=C(F)C=C1 ROJCTGFXGJZWFA-FQEVSTJZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/20—Complexes comprising metals of Group II (IIA or IIB) as the central metal
- B01J2531/26—Zinc
-
- 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
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- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种喹喔啉骨架NN噁唑啉类配体及其合成方法和应用，在喹喔啉的2号位引入手性噁唑啉基团，其结构通式为：其中，R1独立选自于H，Me，Ph；其中，R2独立选自于Ph，tBu，iPr，Bn，Me。制备方法包括以2‑喹喔啉羧酸为原料，或以4，5‑二甲基苯二胺为原料，或以4，5‑二溴苯二胺为原料，生成新型喹喔啉骨架NN噁唑啉类配体。与现有技术相比，本发明的合成扩充了手性噁唑啉配体的范围，为不对称催化领域提供了一种新型骨架的配体。本发明所述的合成方法简单高效、合成条件温和、易于操作且重复性好。制得的手性配体在用于氧化吲哚的不对称氟化反应时，具有较高的对映选择性和产率。
Description
技术领域
本发明涉及有机合成领域，尤其是涉及一种新型喹喔啉骨架NN噁唑啉配体的合成方法和应用。
背景技术
噁唑啉类配体是近年来应用较为广泛的配体之一。自1986年Brunner小组开发了第一个含手性噁唑啉的配体(Pyox)以来(Journal of Organometallic Chemistry 1986,316,C1-C3.)，多种含不同骨架的噁唑啉类配体已经广泛合成应用于不对称催化反应中并取得了巨大的成功(Chemical Society Reviews 2018,47(5),1783-1810.)。
除广泛应用的以吡啶为骨架的噁唑啉配体(Pyox、Pybox)外，以吡嗪为骨架的噁唑啉类配体在相关文献中报道出来，并且在一些反应中表现出良好的催化性能。2015年Correia教授课题组描述了一种手性Pyrabox配体促进高度区域选择性和对映选择性钯催化的未活化三取代无环烯烃的Heck芳基化反应，以提供全碳四元立体中心。(AngewandteChemie,International Edition 2015,54(47),14036-14039.)。
鉴于手性噁唑啉类配体在不对称催化领域广泛而高效的应用，开发含有新型骨架的噁唑啉配体具有重要的理论意义和潜在的应用价值。尽管以吡嗪为骨架的噁唑啉类配体已被合成出来，但现有配体共轭体系比较小，取代位点比较少，结果不够稳定，空间调控能力较差。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种喹喔啉骨架NN噁唑啉类配体及其合成方法和应用，该喹喔啉骨架NN噁唑啉类配体是在喹喔啉骨架2号位引入噁唑啉，对现有的噁唑啉配体库进行扩展，有望能应用在不对称催化领域，而且合成条件温和、易于操作且重复性好。
本发明的目的可以通过以下技术方案来实现：
一种喹喔啉骨架NN噁唑啉类配体，在喹喔啉的2号位引入手性噁唑啉，其结构通式为：
其中，R1独立选自于H，Me，Ph；
其中，R2独立选自于Ph，tBu，iPr，Bn，Me。
本发明还提供了上述配体的制备方法
方法1.当R1为H、R2为Ph，tBu，iPr，Bn，Me时，所述的喹喔啉骨架NN噁唑啉类配体为喹喔啉骨架-手性噁唑啉配体，其合成路线如下：
S11、在N2氛围下，将手性氨基醇加入2-喹喔啉羧酸、N-甲基吗啡啉、氯甲酸异丁酯的二氯甲烷混合溶液中，在室温下反应6-8个小时；
S12、在N2氛围下，-78℃下将二乙胺基三氟化硫(DAST)加入酰胺中间体的二氯甲烷混合溶液中，室温下反应5-7小时得到目标产物。
进一步地，所述的2-喹喔啉羧酸、N-甲基吗啡啉、氯甲酸异丁酯、手性氨基醇的摩尔比为1:1.2:1.2:1.1；
所述酰胺中间体和二乙胺基三氟化硫(DAST)的摩尔比为1:1.6。
方法2.当R1为Me、R2为Ph时，所述的喹喔啉骨架NN噁唑啉类配体为6,7-二甲基喹喔啉骨架-手性噁唑啉配体，其合成路线如下：
S21、在N2氛围下，将4，5-二甲基苯二胺和丙酮醛的甲醇溶液置于预热的40℃油浴中反应24h；
S22、在N2氛围下，将所得2，6，7-三甲基喹喔啉置于1，4-二氧六环溶液中，加入二氧化硒氧化，在100℃下回流4h得到6,7-二甲基喹喔啉-2-甲醛；
S23、在N2氛围下，将6,7-二甲基喹喔啉-2-甲醛、碘单质、碳酸钾、手性氨基醇依次加入无水叔丁醇溶液中，在70℃下反应16h得到目标产物。
进一步地，所述的4，5-二甲基苯二胺和丙酮醛的摩尔比为1:3.7；
所述2，6，7-三甲基喹喔啉与二氧化硒的摩尔比为1:1.5；
所述6,7-二甲基喹喔啉-2-甲醛、碘单质、碳酸钾、手性氨基醇的摩尔比为1:2:3:1.1。
方法3.当R1为Ph、R2为Ph时，所述的喹喔啉骨架NN噁唑啉类配体为6,7-二苯基喹喔啉骨架-手性噁唑啉配体，其合成路线如下：
S31、在N2氛围下，将4，5-二溴苯二胺、苯硼酸、四三苯基膦钯、2M碳酸钾依次加入无水甲苯溶液中，在80℃下反应24h得到双苯基取代的苯二胺中间体；
S32、在N2氛围下，将双苯基取代的苯二胺中间体和丙酮醛的甲醇溶液置于预热的40℃油浴中反应24h得到2-甲基-6,7-二苯基喹喔啉；
S33、在N2氛围下，将所得2-甲基-6,7-二苯基喹喔啉置于1,4-二氧六环溶液中，加入二氧化硒氧化，在100℃下回流4h得到6,7-二苯基喹喔啉-2-甲醛；
S34、在N2氛围下，将6,7-二苯基喹喔啉-2-甲醛、碘单质、碳酸钾、手性氨基醇依次加入无水叔丁醇溶液中，在70℃下反应16h得到目标产物。
进一步地，所述的4，5-二溴苯二胺、苯硼酸、四三苯基膦钯的摩尔比为1:2.5:0.03；
所述双苯基取代的苯二胺中间体和丙酮醛的摩尔比为1:3.7；
所述2-甲基-6,7-二苯基喹喔啉和二氧化硒的摩尔比为1:1.5；
所述6,7-二苯基喹喔啉-2-甲醛、碘单质、碳酸钾、手性氨基醇的摩尔比为1:2:3:1.1。
本发明还提供一种如权利要求1所述喹喔啉骨架NN噁唑啉类配体的应用，所述配体用于氧化吲哚的不对称氟化反应，氟化产物具有如下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素中的一种；R2独立选自于苯基、甲苯、氟苯中的一种。
所述氧化吲哚的不对称氟化的方法为：无水无氧操作，氮气氛围下在无水乙醚中，将所述配体与碘化锌在室温下搅拌1-2h，然后依次加入氧化吲哚和N-氟代二苯磺酰亚胺，反应0.5h小时后直接将反应溶液旋干后200-300目硅胶过柱(PE/EA＝45:1)，其中所述配体、碘化锌、氧化吲哚和N-氟代二苯磺酰亚胺的摩尔比为1：1：20：22。
所述的氧化吲哚具有以下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素中的一种；R2独立选自于苯基、甲苯、氟苯中的一种。所述的氧化吲哚的合成方法参考文献(J.Am.Chem.Soc.2005,127,29,10164–10165)。
与现有技术相比，本发明具有以下优点：
(1)本发明首次研发了以喹喔啉(或称苯并吡嗪)为骨架的噁唑啉类配体，相较于吡嗪来说，喹喔啉具有更大的共轭体系、更加刚性的结构、更多的取代位点等特点，含有喹喔啉骨架的噁唑啉配体预期有更稳定的性能、更灵活多样的电子和空间调控能力。本发明基于上述研发背景以及目标配体良好的应用前景，开发出一种喹喔啉骨架NN噁唑啉类配体的合成方法。
(2)本发明以市场上廉价的2-喹喔啉羧酸为原料，将其与手性氨基醇缩合，生成酰胺中间体，然后通过二乙胺基三氟化硫(DAST)的作用关环得到喹喔啉骨架-手性噁唑啉配体。
(3)本发明以4，5-二甲基苯二胺为原料，与丙酮醛反应得到2，6，7-三甲基喹喔啉，在二氧化硒的氧化下生成6,7-二甲基喹喔啉-2-甲醛，通过碘单质和碳酸钾的作用与手性氨基醇反应，生成6,7-二甲基喹喔啉骨架-手性噁唑啉配体。
(4)本发明以4，5-二溴苯二胺为原料与苯硼酸偶联生成双苯基取代的苯二胺中间体，其与丙酮醛反应得到2-甲基-6,7-二苯基喹喔啉，在二氧化硒的氧化下生成6,7-二苯基喹喔啉-2-甲醛，通过碘单质和碳酸钾的作用与手性氨基醇反应，生成6,7-二苯基喹喔啉骨架-手性噁唑啉配体。
(5)本发明上述三种合成方法，均实现了在喹喔啉骨架2号位引入噁唑啉，扩充了手性噁唑啉配体的范围，为不对称催化领域提供了一种新型骨架的配体。本发明所述的合成方法简单高效、合成条件温和、易于操作且重复性好。制得的手性配体在用于氧化吲哚的不对称氟化反应时，具有较高的对映选择性和产率。
附图说明
图1是实施例1中3a的单晶衍射(X-ray)数据的示意图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
以下实施例中采用的所有溶剂、试剂、金属盐都是从商业来源购买。
所有目标化合物采用NMR(1H)、NMR(13C)、NMR(19F)、Rudolph Research Analytical旋光仪在1dm比色杯中测定数据表征。
以下实施例中的目标产物的收率均为分离产率。
以下实施例中的目标产物的对映选择性通过HPLC色谱分析测定。
实施例1
喹喔啉骨架-手性噁唑啉配体的合成步骤：
步骤(1)按以下反应方程式反应：
具体操作步骤为：
无水无氧操作，N2气氛围下将2-喹喔啉羧酸加入50ml Schlenk反应瓶中，加入无水二氯甲烷和N-甲基吗啡啉，在0℃下加入氯甲酸异丁酯，反应五分钟后，在氮气保护下，加入手性氨基醇,回复至室温下反应。6-8h小时后加入冰水，后用DCM萃取3次，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝3:1)。所述2-喹喔啉羧酸、N-甲基吗啡啉、氯甲酸异丁酯、手性氨基醇的摩尔比为1:1.2:1.2:1.1；
(R)-N-(2-羟基-1-苯乙基)喹喔啉-2-甲酰胺；白色固体；90％yield；1H NMR(400MHz,Chloroform-d)δ9.59(s,1H),8.64(d,J＝7.8Hz,1H),8.16–8.05(m,2H),7.86–7.74(m,2H),7.46–7.40(m,2H),7.39–7.32(m,2H),7.32–7.27(m,1H),5.35(dt,J＝7.8,5.0Hz,1H),4.07(t,J＝4.7Hz,2H),3.10(d,J＝5.7Hz,1H).13C NMR(101MHz,Chloroform-d)δ163.59,143.91,143.89,143.24,140.26,138.82,131.78,130.95,129.77,129.50,129.04,128.11,126.94,66.35,56.04.
(S)-N-(1-羟基-3,3-二甲基丁烷-2-基)喹喔啉-2-甲酰胺；白色固体；80％yield；1H NMR(400MHz,Chloroform-d)δ9.67(s,1H),8.17(dd,J＝19.7,8.1Hz,3H),7.87(q,J＝6.5Hz,2H),4.15–4.00(m,2H),3.77(t,J＝9.8Hz,1H),1.08(s,9H).13C NMR(101MHz,Chloroform-d)δ164.09,143.85,143.84,143.69,143.27,140.07,140.06,131.58,130.78,129.70,129.33,129.31,62.69,60.02,60.00,34.11,27.05.
(S)-N-(1-羟基-3-甲基丁烷-2-基)喹喔啉-2-甲酰胺；白色固体；83％yield；1HNMR(400MHz,Chloroform-d)δ9.66(s,1H),8.15(dd,J＝21.1,7.9Hz,3H),7.85(p,J＝6.9Hz,2H),4.09–3.97(m,1H),3.94–3.78(m,2H),2.13(hept,J＝7.1Hz,1H),1.07(t,J＝7.7Hz,6H).13C NMR(101MHz,Chloroform-d)δ163.62,143.84,143.32,140.23,131.73,130.95,129.67,129.49,66.73,48.04,17.21.
(S)-N-(1-羟基-3-苯基丙-2-基)喹喔啉-2-甲酰胺；白色固体；81％yield；1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.25(d,J＝8.2Hz,1H),8.18(d,J＝8.0Hz,1H),8.13–8.05(m,1H),7.90–7.81(m,2H),7.32(d,J＝4.3Hz,5H),4.46(dt,J＝8.2,4.7Hz,1H),3.87(q,J＝5.3,4.5Hz,1H),3.79(q,J＝5.8,5.4Hz,1H),3.08(d,J＝7.2Hz,2H),2.55(s,1H).13C NMR(101MHz,Chloroform-d)δ163.69,144.01,143.89,143.33,140.33,137.56,131.78,130.97,129.80,129.59,129.47,128.83,126.92,64.05,53.26,37.36.
(S)-N-(1-羟基丙-2-基)喹喔啉-2-甲酰胺；白色固体；92％yield；1H NMR(400MHz,Chloroform-d)δ9.58(d,J＝2.0Hz,1H),8.16–8.07(m,2H),8.04(d,J＝7.6Hz,1H),7.86–7.74(m,2H),4.34(dq,J＝12.8,6.4,5.7Hz,1H),3.85(dt,J＝10.1,4.6Hz,1H),3.73(dt,J＝11.0,5.4Hz,1H),3.33(dq,J＝11.0,5.7Hz,1H),1.36(d,J＝6.7Hz,3H).13CNMR(101MHz,Chloroform-d)δ163.52,143.77,143.74,143.32,140.17,131.67,130.89,129.63,129.40,66.53,47.97,17.19.
步骤(2)按以下反应方程式反应：
具体操作步骤为：
在氮气氛围下，将酰胺中间2体加入到100ml圆底烧瓶中，加入40ml无水二氯甲烷，之后-78℃下将DAST加入酰胺中间体的二氯甲烷混合溶液中，所述酰胺中间2体和二乙胺基三氟化硫(DAST)的摩尔比为1:1.6。室温下反应5-7小时后向反应体系加入1.5equiv碳酸钾搅拌10分钟，用DCM萃取3次，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝5:1)。
(R)-4-苯基-2-(喹啉-2-基)-4,5-二氢噁唑；白色固体；96％yield；化合物(R)-4-苯基-2-(喹啉-2-基)-4,5-二氢噁唑的结构鉴定是基于化合物的质谱、相关核磁共振谱(如上所述)以及X-ray单晶衍射数据(见图1)分析而确定的。
化合物(R)-4-苯基-2-(喹啉-2-基)-4,5-二氢噁唑1H、13C NMR和X-ray数据如下：
1H NMR(400MHz,Chloroform-d)δ8.33–8.25(m,3H),7.88(d,J＝8.2Hz,1H),7.82–7.75(m,1H),7.63(t,J＝7.5Hz,1H),7.43–7.29(m,5H),5.52(t,J＝9.4Hz,1H),4.99(t,J＝9.4Hz,1H),4.48(t,J＝8.6Hz,1H).13C NMR(101MHz,Chloroform-d)δ162.58,145.24,143.26,141.59,141.54,141.31,131.75,130.98,130.34,129.48,129.07,128.14,126.94,75.60,70.78.
(R)-4-苯基-2-(喹啉-2-基)-4,5-二氢噁唑的X-ray数据：
(S)-4-(叔丁基)-2-(喹喔啉-2-基)-4,5-二氢噁唑；白色固体；86％yield；1H NMR(400MHz,Chloroform-d)δ8.25(dd,J＝13.4,8.9Hz,3H),7.86(d,J＝8.2Hz,1H),7.79–7.72(m,1H),7.61(t,J＝7.5Hz,1H),4.56(t,J＝9.6Hz,1H),4.42(t,J＝8.5Hz,1H),4.20(dd,J＝10.3,8.1Hz,1H),1.01(s,9H).13C NMR(101MHz,Chloroform-d)δ161.23,145.28,143.12,141.85,141.48,131.48,130.81,130.30,129.42,69.67,34.25,26.05.
(S)-4-(异丙基)-2-(喹喔啉-2-基)-4,5-二氢噁唑；白色固体；90％yeild；1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.15(dd,J＝21.1,7.9Hz,3H),7.85(p,J＝6.9Hz,2H),4.09–3.97(m,1H),3.94–3.78(m,2H),2.13(hept,J＝7.1Hz,1H),1.07(t,J＝7.7Hz,6H).13C NMR(101MHz,Chloroform-d)δ163.62,143.84,143.32,140.23,131.73,130.95,129.67,129.49,66.73,48.04,17.21.
(S)-4-苄基-2-(喹喔啉-2-基)-4,5-二氢噁唑；白色固体；93％yield；1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),8.29–8.13(m,2H),7.84(tt,J＝7.6,5.4Hz,2H),7.37–7.25(m,6H),4.77(qd,J＝8.6,5.4Hz,1H),4.54(t,J＝9.0Hz,1H),4.33(t,J＝8.1Hz,1H),3.33(dd,J＝13.8,5.2Hz,1H),2.84(dd,J＝13.8,8.8Hz,1H).13C NMR(101MHz,Chloroform-d)δ161.90,145.07,143.18,141.68,141.54,137.48,131.66,130.94,130.33,129.45,129.39,128.80,126.88,41.65.
(S)-4-甲基-2-(喹喔啉-2-基)-4,5-二氢噁唑；白色固体；88％yield；1H NMR(400MHz,Chloroform-d)δ9.54(s,1H),8.24(d,J＝7.9Hz,1H),8.14(d,J＝7.7Hz,1H),7.87–7.78(m,2H),4.69(t,J＝8.8Hz,1H),4.55(h,J＝7.2Hz,1H),4.14(t,J＝8.1Hz,1H),1.45(d,J＝6.7Hz,3H).13C NMR(101MHz,Chloroform-d)δ161.33,144.94,143.08,141.71,141.49,131.54,130.84,130.27,129.36,74.87,62.76,21.36.
实施例2
6,7-二甲基喹喔啉手性噁唑啉配体的合成步骤：
步骤(1)按以下反应方程式反应：
具体操作步骤为：
无水无氧操作，N2气氛围下将摩尔比为1:3.7的化合物4和丙酮醛的甲醇溶液加入到25ml Schlenk瓶中，置于预热的40℃油浴中反应24h。后处理加水淬灭，用EA萃取3次，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝20:1)。
2,6,7-三甲基喹喔啉；淡黄色固体；55％yield；1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.73(d,J＝18.3Hz,2H),2.69(s,3H),2.43(s,6H).13C NMR(101MHz,Chloroform-d)δ152.68,145.02,140.98,140.42,139.90,139.22,128.19,127.75,22.46,20.38,20.22.
步骤(2)按以下反应方程式反应：
在氮气氛围下，将上述步骤获得的化合物5和二氧化硒加入三颈烧瓶中，化合物5与二氧化硒的摩尔比为1:1.5，用注射器注入干燥1，4-二氧六环。100℃下回流24h,等反应结束后，体系恢复至室温直接过滤，收集滤液旋干，过柱纯化(PE/EA＝10:1)。
6,7-二甲基喹喔啉-2-甲醛；白色固体；85％yield；1H NMR(400MHz,Chloroform-d)δ10.21(s,1H),9.29(s,1H),7.92(d,J＝12.7Hz,2H),2.53(d,J＝2.9Hz,6H).13C NMR(101MHz,Chloroform-d)δ193.02,145.40,144.45,143.54,142.16,141.81,140.97,129.32,128.62,20.84,20.52.
步骤(3)按以下反应方程式反应：
向500mL圆底烧瓶中加入上述步骤获得的化合物6、t-BuOH、手性氨基醇、在N2氛围下将混合物在30℃搅拌2小时；添加K2CO3(3.0equiv)和I2(2.0equiv)，并将混合物在70℃加热16h；冷却至环境温度后，将反应混合物用饱和Na2S2O3水溶液淬灭，这导致溶液从暗红色变为浅黄色，加入H2O淬灭，用DCM萃取三次，无水MgSO4干燥，过滤，收集滤液旋干直接硅胶柱过柱进行(PE/EA＝8:1)纯化。其中所述化合物6、碘单质、碳酸钾、手性氨基醇的摩尔比为1:2:3:1.1。
(R)-2-(6,7-二甲基喹喔啉-2-基)-4-苯基-4,5-二氢噁唑；黄色固体；65％yield；1H NMR(400MHz,Chloroform-d)δ9.54(s,1H),8.00(d,J＝1.3Hz,1H),7.89(s,1H),7.40–7.28(m,5H),5.54(dd,J＝10.3,8.6Hz,1H),4.96(dd,J＝10.3,8.5Hz,1H),4.46(t,J＝8.6Hz,1H),2.50(d,J＝4.9Hz,6H).13C NMR(101MHz,Chloroform-d)δ162.84,144.36,142.81,142.31,141.69,141.51,140.69,140.54,129.25,129.02,128.46,128.05,126.95,75.48,70.74,20.68,20.57.
实施例3
6,7-二苯基喹喔啉手性噁唑啉配体的合成步骤：
步骤(1)按以下反应方程式反应：
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在氮气氛围下将化合物8、苯基硼酸和Pd(PPh3)4溶解在甲苯中，所述化合物8、苯基硼酸、四三苯基膦钯的摩尔比为1:2.5:0.03。将2.0M K2CO3水溶液添加到甲苯溶液中。并且，将反应体系在85℃下搅拌24小时。待到反应结束后，体系恢复至室温下，向反应体系中加入水淬灭，用DCM萃取三次，无水Na2SO4干燥，过滤收集滤液，滤液旋干后通过硅胶柱过柱(PE/EA＝2:1)纯化。
[1,1':2',1”-三联苯]-4',5'-二胺；棕褐固体；70％yield；1H NMR(400MHz,Chloroform-d)δ7.32–7.14(m,10H),6.84(s,2H),3.55(s,4H).13C NMR(101MHz,Chloroform-d)δ141.75,134.13,132.59,132.16,132.06,129.97,128.65,128.53,127.77,125.88,118.89.
步骤(2)按以下反应方程式反应：
无水无氧操作，N2气氛围下将上述步骤制得的化合物9和丙酮醛的甲醇溶液加入到25ml Schlenk瓶中，置于预热的40℃油浴中反应24h。后处理加水淬灭，用EA萃取3次，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝40:1)。所述化合物9和丙酮醛的摩尔比为1:3.7。
2-甲基-6,7-二苯基喹喔啉；白色固体；58％yield；1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.12(d,J＝17.2Hz,2H),7.33–7.21(m,11H),2.82(s,3H).13C NMR(101MHz,Chloroform-d)δ141.75,134.13,132.59,132.16,132.06,129.97,128.65,128.53,127.77,125.88,118.89.
步骤(3)按以下反应方程式反应：
在氮气氛围下，将上述步骤制得的化合物10和二氧化硒加入三颈烧瓶中，用注射器注入干燥1，4-二氧六环。100℃下回流24h,等反应结束后，体系恢复至室温直接过滤，收集滤液旋干，过柱纯化(PE/EA＝10:1)。所述化合物10和二氧化硒的摩尔比为1:1.5；
2-甲基-6,7-二苯基喹喔啉；橘红色固体；80％yield；1H NMR(400MHz,Chloroform-d)δ10.30(s,1H),9.43(s,1H),8.29(s,1H),8.25(s,1H),7.33–7.27(m,7H),7.26–7.22(m,3H).13C NMR(101MHz,Chloroform-d)δ192.85,146.70,146.33,144.97,143.84,142.98,141.35,139.72,139.68,131.48,130.68,129.96,128.37,127.93,127.80.
步骤(4)按以下反应方程式反应：
向500mL圆底烧瓶中加入上述步骤制得的化合物11、t-BuOH、手性氨基醇、在N2氛围下将混合物在30℃搅拌2小时；添加K2CO3(3.0equiv)和I2(2.0equiv)，并将混合物在70℃加热16h；冷却至环境温度后，将反应混合物用饱和Na2S2O3水溶液淬灭，这导致溶液从暗红色变为浅黄色，加入H2O淬灭，用DCM萃取三次，无水MgSO4干燥，过滤，收集滤液旋干直接硅胶柱过柱进行(PE/EA＝8:1)纯化。所述化合物11、碘单质、碳酸钾、手性氨基醇的摩尔比为1:2:3:1.1。
(R)-2-(6,7-二苯基喹喔啉-2-基)-4-苯基-4,5-二氢噁唑；黄色固体；61％yield；1H NMR(400MHz,Chloroform-d)δ9.67(s,1H),8.34(d,J＝2.1Hz,1H),8.23(d,J＝2.0Hz,1H),7.40(d,J＝7.5Hz,5H),7.29(s,6H),7.23(d,J＝8.3Hz,4H),5.59(t,J＝9.5Hz,1H),5.01(t,J＝9.5Hz,1H),4.55–4.46(m,1H).13C NMR(101MHz,Chloroform-d)δ173.08,169.93,164.04,163.08,132.55,131.42,129.35,129.11,127.98,127.34,126.32,109.07,70.19,21.66,7.62.
应用实施例
将上述实施例1制得的手性喹喔啉骨架NN噁唑啉类配体用于氧化吲哚的不对称氟化反应
按以下反应方程式反应：
具体操作步骤为:
无水无氧操作，氮气氛围下在1mL无水乙醚中，0.005mmol实施例1制得的手性配体3a与0.005mmol碘化锌在室温下搅拌1-2h，然后依次加入0.1mmol氧化吲哚和0.11mmol N-氟代二苯磺酰亚胺，室温下反应0.5h小时后直接将反应溶液旋干后200-300目硅胶过柱(PE/EA＝45:1)。化合物14的对映选择性通过高效液相色谱分析测定。
叔丁基(S)-3-氟-2-氧代-3-苯二氢吲哚-1-羧酸盐，白色固体；89％ee；95％yield(31mg,0.095mmol)；1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝8.3Hz,1H),7.51(t,J＝8.1Hz,1H),7.38(dd,J＝8.2,5.0Hz,6H),7.29(d,J＝7.4Hz,1H),1.62(s,9H).13C NMR(101MHz,Chloroform-d)δ170.40,170.15,149.05,141.15,141.10,135.90,135.63,132.01,131.98,129.68,129.66,128.75,126.44,126.40,126.38,125.78,125.60,125.48,125.45,115.81,115.80,93.75,91.88,85.19,28.16.19F NMR(376MHz,Chloroform-d)δ-145.36.
叔丁基(S)-3-氟-5-甲基-2-氧代-3-苯二氢吲哚-1-羧酸盐，白色固体；95％ee；99％yield(34mg,0.098mmol)；[α]D20＝+126.88.0(c＝0.093,CHCl3)；1H NMR(400MHz,Chloroform-d)δ7.87(dd,J＝8.4,2.5Hz,1H),7.42–7.28(m,6H),7.17(s,1H),2.36(s,3H),1.61(s,9H).13C NMR(101MHz,Chloroform-d)δ170.55,170.31,149.09,138.74,138.68,136.07,135.79,135.34,135.31,132.50,132.47,129.58,129.56,129.04,128.71,126.72,126.38,126.32,125.73,125.55,115.59,115.57,93.93,92.07,84.99,77.35,28.16,21.11.19F NMR(376MHz,Chloroform-d)δ-145.63.
叔丁基(S)-3,5-二氟-2-氧代-3-苯二氢吲哚-1-羧酸盐,白色固体；95％ee；94％yield(33mg,0.094mmol)；1H NMR(400MHz,Chloroform-d)δ8.02(dt,J＝8.1,3.4Hz,1H),7.45–7.32(m,5H),7.21(t,J＝8.9Hz,1H),7.12–7.06(m,1H),1.61(s,9H).13C NMR(101MHz,Chloroform-d)δ169.98,169.74,159.06,149.00,135.34,135.07,129.92,129.90,128.90,127.43,127.35,127.25,127.17,126.23,126.17,118.84,118.81,118.61,118.58,117.50,117.48,117.42,117.41,113.80,113.56,91.59,85.42,28.14,1.16.19F NMR(376MHz,Chloroform-d)δ-115.92,-146.47.
叔丁基(S)-3,7-二氟-2-氧代-3-苯二氢吲哚-1-羧酸盐,白色固体；90％ee；95％yield(32.8mg,0.095mmol)；1H NMR(400MHz,Chloroform-d)δ7.44–7.32(m,5H),7.28(q,J＝1.3Hz,1H),7.18(dt,J＝6.3,2.1Hz,1H),1.60(s,9H).13C NMR(101MHz,Chloroform-d)δ170.00,169.75,150.09,147.57,147.12,135.33,135.06,129.90,129.88,128.88,126.75,126.72,126.68,126.65,126.18,126.12,122.27,122.23,120.37,120.34,120.17,120.14,92.08,85.91,27.84.19F NMR(376MHz,Chloroform-d)δ-117.75,-146.01.
叔丁基(S)-3-氟-2-氧代-3-(对甲苯基)二氢吲哚-1-羧酸盐,白色固体；92％ee；96％yield(32.8mg,0.096mmol)；1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝8.3Hz,1H),7.50(t,J＝8.1Hz,1H),7.37(d,J＝7.7Hz,1H),7.30–7.23(m,4H),7.19(d,J＝8.0Hz,2H),2.36(s,3H),1.61(s,9H).13C NMR(101MHz,Chloroform-d)δ170.55,170.30,149.10,141.10,141.05,139.79,139.77,132.92,132.65,131.92,131.89,129.44,126.46,126.41,126.37,125.84,125.66,125.42,125.39,115.77,115.76,93.71,91.85,85.09,28.16,27.56,21.37.19F NMR(376MHz,Chloroform-d)δ-114.32.
叔丁基(S)-3-氟-5-甲氧基-2-氧代-3-(对甲苯基)二氢吲哚-1-羧酸盐,白色固体；93％ee；98％yield(36.4mg,0.098mmol)；1H NMR(400MHz,Chloroform-d)δ7.92(dd,J＝8.9,2.3Hz,1H),7.25(dd,J＝5.6,2.8Hz,3H),7.19(d,J＝8.0Hz,2H),7.05–6.99(m,1H),6.90(d,J＝3.2Hz,1H),3.79(s,3H),2.35(s,3H),1.60(s,9H).13C NMR(101MHz,Chloroform-d)δ170.62,170.36,157.50,157.47,149.17,139.79,139.77,134.29,134.24,132.92,132.64,129.45,126.85,126.68,126.41,126.35,117.46,117.43,116.92,116.90,111.47,93.95,92.08,84.87,55.87,28.17,21.36,1.16.19F NMR(376MHz,Chloroform-d)δ-145.31.
叔丁基(S)-3,5-二氟-2-氧代-3-(对甲苯基)二氢吲哚-1-羧酸盐,白色固体；96％ee；93％yield(33.4mg,0.093mmol)；1H NMR(400MHz,Chloroform-d)δ8.04–7.99(m,1H),7.25–7.18(m,5H),7.09(ddd,J＝7.2,2.8,1.9Hz,1H),2.36(s,3H),1.60(s,9H).13C NMR(101MHz,Chloroform-d)δ170.13,169.88,149.04,140.07,140.05,136.99,136.97,132.37,132.09,129.57,127.51,127.43,127.33,126.25,126.19,118.73,118.70,118.50,118.47,117.44,117.36,113.77,113.53,85.31,28.13,21.37.19F NMR(376MHz,Chloroform-d)δ-116.10(d,J＝2.0Hz),-145.64(d,J＝2.2Hz).
叔丁基(S)-3-氟-3-(4-氟苯基)-2-氧二氢吲哚-1-羧酸盐,白色固体；90％ee；98％yield(33.8mg,0.098mmol)；1H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝8.2,1.3Hz,1H),7.56–7.49(m,1H),7.42–7.33(m,3H),7.30(dt,J＝7.5,1.0Hz,1H),7.07(ddd,J＝9.0,8.0,0.9Hz,2H),1.62(s,9H).13C NMR(101MHz,Chloroform-d)δ170.24,169.99,164.91,162.45,148.97,141.15,141.10,132.23,132.19,131.66,128.78,128.72,128.69,128.64,126.37,125.56,125.53,125.32,125.15,115.93,115.91,115.71,93.25,91.38,85.32,28.15.19F NMR(376MHz,Chloroform-d)δ-111.56,-142.96.
叔丁基(S)-3-氟-3-(4-氟苯基)-5-甲氧基-2-氧二氢吲哚-1-羧酸盐,白色固体；92％ee；95％yield(35.7mg,0.095mmol)；1H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝9.0,1.3Hz,1H),7.39–7.33(m,2H),7.11–7.01(m,3H),6.90(t,J＝2.4Hz,1H),3.80(s,3H),1.61(s,9H).13C NMR(101MHz,Chloroform-d)δ170.32,170.06,157.59,157.57,149.04,134.30,134.25,131.67,131.42,128.72,128.67,128.64,128.58,126.36,126.18,117.62,117.59,117.08,117.07,115.95,115.73,111.56,93.50,91.62,85.09,55.91,28.16.19FNMR(376MHz,Chloroform-d)δ-111.53,-143.83.
从上述应用实例可以看出，将本发明制得的手性配体在用于氧化吲哚的不对称氟化反应时，具有较高的对映选择性和产率。
本发明提供了一种新型喹喔啉骨架的NN噁唑啉配体的合成方法和应用，该方法简单高效、合成条件温和、易于操作且重复性好。本发明为不对称催化领域提供了一种新型的噁唑啉配体，在不对称催化氧化吲哚的氟化反应中表现出高效的催化活性，其在不对称催化领域有着明显的潜在价值。上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用发明。对于噁唑啉配体结构通式中的R1范围不局限于H、甲基、苯基，它适用于各种烷基和芳基。对于结构通式中的R2基团不局限于苯基、苄基、异丙基、叔丁基、甲基，它适应于一系列手性或消旋氨基醇，不脱离本发明结构通式范畴所做出的改进和修改都应该在本发明的保护范围之内。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
Claims (6)
1.一种喹喔啉骨架NN噁唑啉类配体，其特征在于，其结构式为：
。
2.一种如权利要求1所述喹喔啉骨架NN噁唑啉类配体的合成方法，其特征在于，其合成方法如下：
S11、在N2氛围下，将β-氨基苯乙醇加入2-喹喔啉羧酸、N-甲基吗啡啉、氯甲酸异丁酯的二氯甲烷混合溶液中，在室温下反应6-8个小时；生成酰胺中间体；
S12、在N2氛围下，-78℃下将二乙胺基三氟化硫加入酰胺中间体的二氯甲烷混合溶液中，室温下反应5-7小时得到目标产物。
3.根据权利要求2所述喹喔啉骨架NN噁唑啉类配体的合成方法，其特征在于，所述的2-喹喔啉羧酸、N-甲基吗啡啉、氯甲酸异丁酯、β-氨基苯乙醇的摩尔比为1:1.2:1.2:1.1；
所述酰胺中间体和二乙胺基三氟化硫的摩尔比为1:1.6。
4.一种如权利要求1所述喹喔啉骨架NN噁唑啉类配体的应用，其特征在于，所述配体用于氧化吲哚的不对称氟化反应，氟化产物具有如下结构通式：
；
其中，R1独立选自于氢、甲基、甲氧基、卤素中的一种；R2独立选自于苯基、甲苯、氟苯中的一种。
5.根据权利要求4所述的一种喹喔啉骨架NN噁唑啉类配体的应用，其特征在于，所述氧化吲哚的不对称氟化反应的方法为：无水无氧操作，氮气氛围下在无水乙醚中，将所述配体与碘化锌在室温下搅拌1-2 h，然后依次加入氧化吲哚和N-氟代二苯磺酰亚胺，反应0.5 h小时后直接将反应溶液旋干后200-300 目硅胶过柱,洗脱剂为PE/EA=45:1，其中所述配体、碘化锌、氧化吲哚和N-氟代二苯磺酰亚胺的摩尔比为1：1：20：22。
6.根据权利要求4所述的一种喹喔啉骨架NN噁唑啉类配体的应用，其特征在于，所述的氧化吲哚具有以下结构通式：
；
其中，R1独立选自于氢、甲基、甲氧基、卤素中的一种；R2独立选自于苯基、甲苯、氟苯中的一种。
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| CN110526795A (zh) * | 2019-08-08 | 2019-12-03 | 河南师范大学 | γ-烯基取代的丁烯内酯或丁烯内酰胺化合物及其不对称合成方法和配体 |
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