CN115703806A - Phosphine ligand with pyrazole-amide skeleton and preparation method and application thereof - Google Patents
Phosphine ligand with pyrazole-amide skeleton and preparation method and application thereof Download PDFInfo
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- CN115703806A CN115703806A CN202110903637.1A CN202110903637A CN115703806A CN 115703806 A CN115703806 A CN 115703806A CN 202110903637 A CN202110903637 A CN 202110903637A CN 115703806 A CN115703806 A CN 115703806A
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- CN
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- Prior art keywords
- pyrazole
- alkyl
- disubstituted
- reaction
- phosphine ligand
- Prior art date
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 239000003446 ligand Substances 0.000 title claims abstract description 91
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 77
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical group NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- -1 palladium Chemical class 0.000 claims abstract description 66
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 28
- 150000003624 transition metals Chemical class 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- 239000000203 mixture Substances 0.000 claims description 48
- 239000011541 reaction mixture Substances 0.000 claims description 48
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000012044 organic layer Substances 0.000 claims description 29
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 27
- 239000003054 catalyst Substances 0.000 claims description 22
- SQTLUXJWUCHKMT-UHFFFAOYSA-N 4-bromo-n,n-diphenylaniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 SQTLUXJWUCHKMT-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 238000006880 cross-coupling reaction Methods 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 14
- 239000012267 brine Substances 0.000 claims description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 12
- 239000012265 solid product Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical class P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000000466 oxiranyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- 208000025174 PANDAS Diseases 0.000 claims description 3
- 208000021155 Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Diseases 0.000 claims description 3
- 235000016496 Panda oleosa Nutrition 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical class ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 2
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- 241000274177 Juniperus sabina Species 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000007333 cyanation reaction Methods 0.000 claims description 2
- 238000007872 degassing Methods 0.000 claims description 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 229950000688 phenothiazine Drugs 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 2
- ZSMRRZONCYIFNB-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[b][1]benzazepine Chemical group C1CC2=CC=CC=C2NC2=CC=CC=C12 ZSMRRZONCYIFNB-UHFFFAOYSA-N 0.000 claims 1
- 240000000220 Panda oleosa Species 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 53
- 229910052763 palladium Inorganic materials 0.000 abstract description 27
- 230000003197 catalytic effect Effects 0.000 abstract description 19
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- 125000005842 heteroatom Chemical group 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 18
- 150000001500 aryl chlorides Chemical class 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 235000011089 carbon dioxide Nutrition 0.000 description 8
- 238000004448 titration Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 7
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- AKJFBIZAEPTXIL-UHFFFAOYSA-N chloro(dicyclohexyl)phosphane Chemical compound C1CCCCC1P(Cl)C1CCCCC1 AKJFBIZAEPTXIL-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical class [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 description 5
- 235000011009 potassium phosphates Nutrition 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JREJQAWGQCMSIY-UHFFFAOYSA-N 1-methyl-pyrazole-5-carboxylic acid Chemical compound CN1N=CC=C1C(O)=O JREJQAWGQCMSIY-UHFFFAOYSA-N 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- VDXLAYAQGYCQEO-UHFFFAOYSA-N 2-chloro-1,3-dimethylbenzene Chemical group CC1=CC=CC(C)=C1Cl VDXLAYAQGYCQEO-UHFFFAOYSA-N 0.000 description 3
- NUFSJKMRPYGNHV-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(2-methylphenyl)-1,3,2-dioxaborolane Chemical compound CC1=CC=CC=C1B1OC(C)(C)C(C)(C)O1 NUFSJKMRPYGNHV-UHFFFAOYSA-N 0.000 description 3
- 101100494773 Caenorhabditis elegans ctl-2 gene Proteins 0.000 description 3
- 101100112369 Fasciola hepatica Cat-1 gene Proteins 0.000 description 3
- 101100005271 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cat-1 gene Proteins 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 150000004074 biphenyls Chemical class 0.000 description 3
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- ANMVTDVBEDVFRB-UHFFFAOYSA-N 1-propan-2-ylpyrazole Chemical compound CC(C)N1C=CC=N1 ANMVTDVBEDVFRB-UHFFFAOYSA-N 0.000 description 2
- 240000004718 Panda Species 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001543 aryl boronic acids Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000005347 biaryls Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- AXMODJGMGVEOES-UHFFFAOYSA-N formaldehyde;morpholine Chemical compound O=C.C1COCCN1 AXMODJGMGVEOES-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- GRWGBABUYDPBCJ-UHFFFAOYSA-N n,n-dicyclohexyl-2-methylpyrazole-3-carboxamide Chemical compound CN1N=CC=C1C(=O)N(C1CCCCC1)C1CCCCC1 GRWGBABUYDPBCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical group 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000003784 tall oil Substances 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 101150116295 CAT2 gene Proteins 0.000 description 1
- 101100392078 Caenorhabditis elegans cat-4 gene Proteins 0.000 description 1
- 101100326920 Caenorhabditis elegans ctl-1 gene Proteins 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical class NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101100342039 Halobacterium salinarum (strain ATCC 29341 / DSM 671 / R1) kdpQ gene Proteins 0.000 description 1
- 241000721662 Juniperus Species 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 101100126846 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) katG gene Proteins 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- BRTALTYTFFNPAC-UHFFFAOYSA-N boroxin Chemical compound B1OBOBO1 BRTALTYTFFNPAC-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- RSAFAYLZKCYUQW-UHFFFAOYSA-N n,n-di(propan-2-yl)carbamoyl chloride Chemical compound CC(C)N(C(C)C)C(Cl)=O RSAFAYLZKCYUQW-UHFFFAOYSA-N 0.000 description 1
- XNBKKRFABABBPM-UHFFFAOYSA-N n,n-diphenylcarbamoyl chloride Chemical compound C=1C=CC=CC=1N(C(=O)Cl)C1=CC=CC=C1 XNBKKRFABABBPM-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- 238000005829 trimerization reaction Methods 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a phosphine ligand with a pyrazole-amide skeleton, and a preparation method and application thereof, wherein the structural formula of the phosphine ligand is as follows:
wherein, R is 1 、R 2 Independently is alkyl or aryl, said R 3 Is alkyl or aryl, said R 4 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 5 、R 6 Alkyl or aryl alone. The phosphine ligand with pyrazole-amide skeleton provided by the invention can form a complex with a stable structure with transition metal such as palladium, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions.
Description
Technical Field
The invention relates to the technical field of organic compounds and synthesis, in particular to a phosphine ligand with a pyrazole-amide framework, and a preparation method and application thereof.
Background
Transition metal-catalyzed cross-coupling reactions, such as Suzuki-Miyaura, juniper mountain (Hiyama), radicular (Negishi), panda (Kumada), and Stille (Stille) cross-coupling reactions, are important and common methods for preparing biaryls and/or related compounds. Among them, ortho-polysubstituted biaryl compounds are important core structures in many natural products, drugs, materials and biologically active entities. However, cross-coupling reactions of ortho-trisubstituted and tetra-substituted biphenyls are extremely challenging. The challenge is that the highly sterically hindered substituents hinder access to the substrate and catalyst, affecting a series of coupling reaction steps from bond scission to bond formation. The synthesis of ortho-trisubstituted biphenyls, and especially ortho-tetrasubstituted biphenyls, has been reported to be very poor, especially when inexpensive and readily available aryl chlorides are used as electrophiles, which requires high catalyst usage and also harsh conditions.
In the suzuki-miyaura cross-coupling reaction, arylboronic acids are the most commonly used nucleophiles. They have high nucleophilicity and thus are susceptible to transmetallation, but they suffer from structural ambiguity. Under anhydrous conditions, boric acid readily undergoes dimerization and trimerization reactions to form anhydrides and boroxines. Boric acid is a mixture of monomers, dimers, and boroxines that readily exist. Different ratios of boric acid to boroxine lead to different reactivity. Therefore, recrystallization purification may be required before using commercially available boric acid. In contrast, arylboronic acid esters are stable in air and moisture and exist only as monomers. Due to their high stability, they are easily purified by chromatography. Moreover, many arylboronic acid esters are liquid at room temperature and can be readily purified by distillation methods. In addition, the hydrolysis reaction of the aryl and heteroaryl borate ester is slow, and the in-situ boron removal reaction can be reduced when the catalytic reaction is carried out. In particular, the stability of some electrophiles with aryl heterocycles is beneficial to reduce the occurrence of in-situ boron removal, and can be beneficial to the synthesis of some products with special structures.
Ligands play a key role in cross-coupling reactions catalyzed by various transition metals, and particularly under the condition of limited transition metal types, the regulation and control of the performances of various transition metal catalysts, such as the activity, the catalytic efficiency and the like of the reaction, are all regulated by introducing different ligands. Organic phosphine compounds are one of the ligands which are relatively commonly used at present. Over the past years of studies on phosphine ligands have shown that small changes in the size, position, steric hindrance, electrical properties, etc. of substituents on the phosphine ligand backbone all have a significant effect on the outcome of the cross-coupling reaction. Of these, common well-known phosphine ligands, such as: tri-tert-butylphosphine of Fu research group, biaryl phosphine ligand of Buchwald research group, ferrocene phosphine ligand of Hartwig research group and phosphine ligand of Beller research group all show excellent catalytic performance in palladium-catalyzed cross-coupling reaction.
Phosphine ligands with pyrazole-carboxamide skeletons are novel ligands in organometallic chemistry, and have the advantages that the ligands are not sensitive to air and humidity, and the electrical property and the spatial structure of the ligands can be changed by changing substituent groups on pyrazole and amide and adjusting substituent groups on nitrogen atoms on the pyrazole; in addition, the coordination performance of the ligand can be changed by changing the substituent group on the phosphorus atom.
There have been some reports of the use of arylboronic acids in palladium-catalyzed highly hindered suzuki-miyaura cross-coupling reactions, but highly hindered (hetero) aryl chlorides and (hetero) arylboronic esters have to date been largely challenging and unsuccessful. One of the reasons is that the borate ester in the (hetero) arylborate ester has lower activity than boric acid, but has larger steric hindrance, and has higher requirements on the structure and the electrical property of a catalytic center during the metal transfer reaction.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a phosphine ligand with a pyrazole-amide skeleton and a preparation method and application thereof, and aims to solve the problems that the existing phosphine ligand for cross-coupling reaction cannot meet the requirements of easiness in preparation, stable structure and poor catalytic activity when being used as a synergist of a transition metal catalyst.
The technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a phosphine ligand having a pyrazole-amide skeleton, wherein the structural formula is as follows:
In a second aspect of the present invention, there is provided a process for preparing a phosphine ligand having a pyrazole-amide skeleton, which comprises the steps of:
preparing an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
reacting the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate with N-bromosuccinimide to obtain a 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
reacting the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate, N-butyllithium and disubstituted phosphine chloride to obtain the phosphine ligand with a pyrazole-amide skeleton.
In a third aspect of the invention, an application of a phosphine ligand with a pyrazole-amide skeleton as a synergist of a transition metal catalyst in cross-coupling reaction is provided.
Has the advantages that: compared with the prior art, the phosphine ligand with pyrazole-amide skeleton provided by the invention can form a complex with a stable structure with transition metal such as palladium, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the pyrazole-amide skeleton and transition metal such as palladium can prepare various synthetic products such as high-steric-hindrance bi- (hetero) aryl compounds, and has great application potential in the synthesis of natural products and medicaments. The phosphine ligand with the pyrazole-amide framework provided by the invention can be widely used for highly difficult transition metal-catalyzed cross-coupling reactions, including Suzuki-Miyaura reaction of (hetero) arylchlorides and (hetero) arylboronates (Sterically hindred Suzuki-Miyaura reaction of (hetero) aryl chlorides with (hetero) aryl boronates esters) for the first time. The catalytic activity of a transition metal catalyst such as a palladium catalyst can be as low as 0.005mol%, the separation yield is as high as 99%, and the method has profound significance in cross-coupling reaction; meanwhile, the functional groups such as ester, ketone, nitrile, aldehyde, methoxyl and the like are compatible. In addition, the phosphine ligand with the pyrazole-amide skeleton has stability to air and moisture, and is easy to store; and the spatial structure and the electric property of the ligand can be adjusted by changing the substituent groups on the pyrazole, so that the coordination performance of the ligand is changed.
The preparation method of the phosphine ligand with the pyrazole-amide skeleton provided by the invention has the advantages of simple and easily obtained raw materials, simple method and high total yield.
The phosphine ligand with the pyrazole-amide framework provided by the invention can be widely used as a synergist of a transition metal catalyst, is used for a cross-coupling reaction to form a complex with a stable structure with a transition metal such as palladium, so that the catalytic activity of the complex is improved during the catalytic reaction of the transition metal such as palladium, and the phosphine ligand is particularly suitable for the cross-coupling reaction catalyzed by the first transition metal, including Suzuki-Miyaura reaction of (hetero) aryl chloride and (hetero) aryl borate, wherein the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.005mol%, and the separation yield is as high as 99%.
Drawings
FIG. 1 is a flow chart of a preparation method of a phosphine ligand with a pyrazole-amide skeleton.
Detailed Description
The invention provides a phosphine ligand with a pyrazole-amide skeleton and a preparation method and application thereof, and the invention is further detailed below in order to make the purpose, technical scheme and effect of the invention clearer and more clear. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a phosphine ligand with a pyrazole-amide skeleton, which has the following structure shown in the formula I:
wherein, R is 1 、R 2 Independently of one another, alkyl or aryl, R 3 Is alkyl or aryl, said R 4 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 5 、R 6 Alkyl or aryl alone.
The phosphine ligands of pyrazole-amide skeletons in the above structural formula I are collectively referred to as 4- (disubstituted phosphino) -N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide skeletons, and particularly preferably, R is R 1 、R 2 Independently is one of C1-C10 alkyl, C3-C10 cycloalkyl, phenyl and pyridyl; the R is 1 -R 2 Cycloalkyl, morpholine, carbazole, benzoxazine, phenothiazine, iminostilbene and sulphenylene connected with C3-C10One of aminodibenzyl; the R is 3 Is one of C1-C10 alkyl, C3-C10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle and phenyl; the R is 4 Is one of hydrogen, C1-10 alkyl, C1-10 alkoxy, phenyl, fluorine and trifluoromethyl; the R is 5 、R 6 And is independently one of phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl.
Further, said R 1 And R 2 The C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, and the C3-C10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C7-C10 cycloalkyl groups;
the R is 3 Wherein the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl, the C3-C10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl, the oxirane ring includes tetrahydrofuran, the oxirane group includes glycidyl, the alkoxyalkyl group includes methoxymethyl, and the oxacycloalkyl group includes tetrahydrofurylmethyl;
the R is 4 The C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, and the C1-C10 alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy groups.
The phosphine ligand of the pyrazole-amide skeleton in the preferred situation can be combined with transition metal such as palladium to obtain a catalytic system with better catalytic effect, and various synthetic products such as high-steric-hindrance bi- (hetero) aryl compounds are prepared.
The phosphine ligand with the pyrazole-amide framework provided by the embodiment of the invention can form a complex with a stable structure with transition metal such as palladium, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the pyrazole-amide skeleton and transition metal such as palladium can be used for preparing various synthetic products such as high-steric-hindrance bi- (hetero) aryl compounds, and has great application potential in the synthesis of natural products and medicaments. The phosphine ligands of the pyrazole-amide frameworks provided by the embodiments of the present invention can be suitable for highly refractory transition metal-catalyzed cross-coupling reactions such as Suzuki-Miyaura reactions of (hetero) arylchlorides and (hetero) arylboronates (Sterically mutated Suzuki-Miyaura reactions of (hetero) aryl chlorides with (hetero) aryl boronates). The catalytic activity of a transition metal catalyst such as a palladium catalyst can be as low as 0.005mol%, the separation yield is as high as 99%, and the method is a first-time Rich simulation of the Suzuki-Miyaura coupling reaction of high-steric-hindrance (hetero) aryl chloride and (hetero) arylboronic acid ester to synthesize tri-and tetra-ortho-polysubstituted bis (hetero) aryl compounds and has profound significance in cross-coupling reaction; meanwhile, the functional groups such as ester, ketone, nitrile, aldehyde, methoxyl and the like are compatible. In addition, the phosphine ligand of the pyrazole-amide skeleton disclosed by the embodiment of the invention has stability to air and moisture and is easy to store; and the space structure and the electric property of the ligand can be adjusted by changing the substituent group on the amide, so that the coordination performance of the ligand is changed.
In some embodiments, there is also provided a method of preparing a phosphine ligand of pyrazole-amide skeleton, as shown in fig. 1, comprising the steps of:
s10, preparing an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
s20, reacting the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate with N-bromosuccinimide to obtain a 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
s30, reacting the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate, N-butyllithium and disubstituted phosphine chloride to obtain the phosphine ligand with a pyrazole-amide skeleton.
As a specific example, the preparation method of the phosphine ligand of pyrazole-amide skeleton comprises the following steps:
s01, dissolving 1-alkyl-1H-pyrazole-5-carboxylic acid in anhydrous chloroform, adding oxalyl chloride at room temperature, dropwise adding dimethylformamide, and heating and refluxing the reaction; concentrating the reaction solution under reduced pressure, dissolving the concentrated mixture in anhydrous chloroform, and cooling to 0 deg.C; adding N, N-disubstituted amine at 0 ℃; then the reaction is stirred at 70 ℃; after the reaction is finished, adding water into the system, and adding ethyl acetate for extraction and separation; then adding ethyl acetate into the water phase for extraction for several times, combining and concentrating the organic phases, and purifying by column chromatography to obtain an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate; or dissolving 1-alkylpyrazole in tetrahydrofuran, adding N-butyllithium dropwise at-75 to-80 ℃ and more preferably-78 ℃, stirring uniformly at room temperature for 30 minutes, subsequently adding N, N-disubstituted carbamoyl chloride at-75 to-80 ℃ and more preferably-78 ℃, and then heating the reaction mixture to room temperature and stirring for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then the organic phase was concentrated. The concentrated mixture was loaded on a silica gel column and then eluted with ethyl acetate/hexane. Concentrating and evaporating the eluent to obtain an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
s02, dissolving the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate in anhydrous dimethylformamide, adding N-bromosuccinimide at room temperature, and stirring the reaction mixture at 80 ℃ for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated and dried under vacuum to give 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate. If solid, the concentrated mixture may be further recrystallized from a solvent and isolated to provide the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate.
S03, dissolving the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate in tetrahydrofuran, adding N-butyllithium at-75 to-80 ℃, more preferably at-78 ℃, uniformly stirring for 20 to 30 minutes, subsequently adding disubstituted phosphine chloride, and reacting at room temperature for 2 to 24 hours. And after the reaction is finished, concentrating the reaction solution under reduced pressure, adding a degassing solvent into the concentrated mixture for washing, filtering and collecting a solid product, and then drying in vacuum to obtain the phosphine ligand with the pyrazole-amide skeleton.
In this example, the phosphine ligand having a pyrazole-amide skeleton is collectively referred to as a 4- (disubstituted phosphino) -N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide skeleton phosphine ligand.
Specifically, in the above step S01, as a specific example, the reaction formula for preparing the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate is as follows:
for better reaction effect, it is preferable that the molar ratio of the 1-alkyl-1H-pyrazole-5-carboxylic acid, oxalyl chloride and N, N-disubstituted amine is 1.0. Further preferably, the 1-alkyl-1H-pyrazole-5-carboxylic acid is dissolved in anhydrous chloroform, oxalyl chloride is added at a ratio of 1.0 to 1.2 at room temperature, followed by dropwise addition of dimethylformamide, and then the reaction is heated to reflux. After the reaction solution was concentrated under reduced pressure, the concentrated mixture was dissolved in anhydrous chloroform and cooled to 0 ℃. The N, N-disubstituted amine was added at 0 ℃ in a ratio of 1.0. The reaction was then left to stir at 70 ℃.
Preferably, after the reaction is finished, adding water to stop the reaction, and adding ethyl acetate to extract and separate; drying with sodium sulfate, concentrating the organic phase, and purifying by column chromatography to obtain N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
it is noted that the molar ratio of the 1-alkyl pyrazole, the N-butyl lithium and the N, N-disubstituted carbamoyl chloride can also be prepared according to the present invention in the range of (1.0-1.1): 1.0. More preferably, the 1-alkyl pyrazole is dissolved in tetrahydrofuran, and n-butyl lithium is added at a ratio of 1.0; subsequently, N-disubstituted carbamoyl chloride is added at a ratio of (1.0-1.1): (1.0-1.1): 1.0 at-75 to-80 ℃, more preferably at-78 ℃, and then the reaction mixture is warmed to room temperature and stirred for 1 hour.
Further preferably, after completion of the reaction, the reaction mixture is concentrated under reduced pressure, and the concentrated mixture is diluted with methylene chloride and the organic layer is washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then the organic phase was concentrated. The concentrated mixture was loaded on a silica gel column and then eluted with ethyl acetate/hexane. Concentrating and evaporating the eluent to obtain the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate, wherein the reaction formula is shown as follows:
specifically, in the above step S02, as a specific example, the reaction formula for preparing the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate is as follows:
for better reaction effect, the molar ratio of the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide to N-bromosuccinimide is preferably 1.0. Further preferably, the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide is dissolved in anhydrous dimethylformamide. N-bromosuccinimide was added at room temperature in a ratio of 1.0.
More preferably, after completion of the reaction, the reaction solution is concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. Purifying by column chromatography to obtain 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate or recrystallizing the concentrated mixture with solvent, and separating to obtain 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
in the above step S03, as a preferable example, in the step of preparing the phosphine ligand of pyrazole-amide skeleton, the molar ratio of the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide, N-butyllithium and disubstituted chlorophosphine is 1.0 (1.0-1.1) to (1.0-1.1). More preferably, the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate is dissolved in tetrahydrofuran, N-butyllithium is added at a temperature of-75 to-80 ℃, more preferably-78 ℃, in a proportion of 1.0 (1.0 to 1.1), and the mixture is stirred uniformly for 30 minutes; then, disubstituted chlorophosphine is added in the proportion of 1.0 (1.0-1.1), and the reaction is stirred for 2-24 hours at room temperature. The reaction formula of S03 is as follows:
it is further preferred that, after the reaction has ended, all solvents are removed under reduced pressure and washed several times with cold methanol, or that degassed methanol or ethanol/water mixtures are added to the concentrated mixture and stirred overnight. The solid product is then collected by filtration and washed with degassed methanol or ethanol/water mixtures to give the phosphine ligand of 4- (disubstituted phosphino) -N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide in powder form.
The preparation method of the phosphine ligand with the pyrazole-amide framework provided by the embodiment of the invention has the advantages of simple and easily obtained raw materials, simple method and high total yield.
In some embodiments, there is also provided the use of the above-described phosphine ligands of pyrazole-amide frameworks as synergists for transition metal catalysts in cross-coupling reactions.
Wherein the cross-coupling reaction includes, but is not limited to, suzuki coupling reaction, sabina coupling reaction, panda coupling reaction, root-shore coupling reaction, boronization reaction and cyanation reaction.
Preferably, the transition metal catalyst is a palladium catalyst.
The 4- (disubstituted phosphino) -N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxanilido phosphine ligand provided by the embodiment of the invention can be widely used as a synergist of a transition metal catalyst, and can be used for a cross-coupling reaction to form a complex with a stable structure with a transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, and particularly, the ligand can be suitable for a Suzuki-Miyaura cross-coupling reaction of high-difficulty high-steric hindrance (hetero) aryl chloride and (hetero) aryl borate, the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.005mol%, and the separation yield is as high as 99%.
In the embodiment of the invention, the room temperature refers to the room temperature of 10-30 ℃.
The invention is further illustrated by the following specific examples.
Example 1: synthesis of 4- (dicyclohexylphosphino) -N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide
1-methyl-1H-pyrazole-5-carboxylic acid (3.15 g, 25.0 mmol) was dissolved in 150 ml of anhydrous chloroform under a nitrogen atmosphere. Oxalyl chloride (2.54 ml, 30.0 mmol) was then added at room temperature, followed by dimethylformamide (five drops) dropwise. The reaction was then heated to reflux for 30 minutes. After the reaction solution was concentrated under reduced pressure, the concentrated mixture was dissolved in anhydrous chloroform and cooled to 0 ℃. N, N-diisopropylamine (7.00 ml, 50.0 mmol) was added at 0 ℃. The reaction was then allowed to stand at 70 ℃ for 30 minutes. Then, 50 ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give the product N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide as a yellow liquid (4.93 g, 94% yield). 1 H NMR(400MHz,CDCl 3 )δ1.08-1.55(m,12H),3.46-4.09(m,5H),6.15-6.18(m,1H),7.35-7.38(m,1H)。
N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide (5.22 g, 25.0 mmol) was dissolved inDry dimethylformamide (50 ml). N-bromosuccinimide (4.45 g, 25.0 mmol) was added at room temperature, and the reaction mixture was stirred at 80 ℃ for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was recrystallized from hexane, isolated as a white solid, and dried under vacuum to give 4-bromo-N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide (6.23 g, 87% yield). 1 H NMR(400MHz,CDCl 3 )δ1.12(d,J＝4.6Hz,3H),1.29(d,J＝4.6Hz,3H),1.54(d,J＝6.2Hz,6H),3.51-3.58(m,1H),3.69-3.78(m,1H),3.81(s,3H),7.38(s,1H)。
4-bromo-N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide (2.88 g, 10.0 mmol) was dissolved in freshly distilled tetrahydrofuran (50 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (10.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodicyclohexylphosphine (2.43 ml, 11.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a degassed ethanol/water (1. The solid product was then collected by filtration and washed with a degassed ethanol/water (1. The solid product was dried under vacuum to give 4- (dicyclohexylphosphino) -N, N-diisopropyl-1-methyl-1H-pyrazole-5-carboxamide cat1 (3.44 g, 85% yield). 1 H NMR(400MHz,CD 2 Cl 2 )δ0.94-2.15(m,34H),3.50-3.60(m,1H),3.66-3.76(m,1H),3.80(s,3H),7.42(s,1H)。
Example 2: synthesis of N, N-dicyclohexyl-4- (dicyclohexylphosphino) -1-methyl-1H-pyrazole-5-carboxamide
1-methyl-1H-pyrazole-5-carboxylic acid (3.15 g, 25.0 mmol) was dissolved in 150 ml of anhydrous chloroform under a nitrogen atmosphere. Oxalyl chloride (2.54 ml, 30.0 mmol) was then added at room temperature, followed by dimethyl formamide dropwiseAmide (five drops). The reaction was then heated to reflux for 30 minutes. After the reaction solution was concentrated under reduced pressure, the concentrated mixture was dissolved in anhydrous chloroform and cooled to 0 ℃. N, N-dicyclohexylamine (9.94 ml, 50.0 mmol) was added at 0 ℃. The reaction was then allowed to stand at 70 ℃ for 30 minutes. Then, 50 ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was pumped off under reduced pressure, the concentrated mixture was loaded on a silica gel column and then eluted with ethyl acetate/hexane. The eluate was concentrated to evaporation, recrystallized from hexane, and isolated as a white solid, and dried under vacuum to give N, N-dicyclohexyl-1-methyl-1H-pyrazole-5-carboxamide (6.07 g, 84% yield). 1 H NMR(400MHz,CDCl 3 )δ1.10-1.28(m,6H),1.57-1.82(m,12H),2.36-2.71(m,2H),2.97-3.27(m,1H),3.38-3.70(m,1H),3.88(s,3H),6.17(d,J＝1.9Hz,1H),7.41(d,J＝1.8Hz,1H)。
N, N-dicyclohexyl-1-methyl-1H-pyrazole-5-carboxamide (4.34 g, 15.0 mmol) was dissolved in anhydrous dimethylformamide (30 ml). N-bromosuccinimide (2.67 g, 15.0 mmol) was added at room temperature and the reaction mixture was stirred at 80 ℃ for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was recrystallized from an ethanol/water mixture and isolated as a white solid, which was dried under vacuum to give 4-bromo-N, N-dicyclohexyl-1-methyl-1H-pyrazole-5-carboxamide (4.50 g, 82% yield). 1 H NMR(400MHz,CDCl 3 )δ0.96-2.00(m,18H),2.51-2.62(m,2H),3.02-3.08(m,1H),3.15-3.23(m,1H),3.75(s,3H),7.33(s,1H)。
4-bromo-N, N-dicyclohexyl-1-methyl-1H-pyrazole-5-carboxamide (1.10 g, 3.0 mmol) was dissolved in freshly distilled tetrahydrofuran (15 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.3 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. The reaction mixture was stirred at-78 ℃ for 30 minAfter a while, chlorodicyclohexylphosphine (0.73 ml, 3.3 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the concentrated mixture was washed with cold degassed methanol, and the white solid product was collected by filtration and dried under vacuum to give N, N-dicyclohexyl-4- (dicyclohexylphosphino) -1-methyl-1H-pyrazole-5-carboxamide cat2 (0.88 g, 60% yield). 1 H NMR(400MHz,CD 2 Cl 2 )δ1.03-1.05(m,4H),1.18(t,J＝7.0Hz,4H),1.23-1.33(m,8H),1.50-1.57(m,6H),1.61-1.64(m,6H),1.68-1.71(m,6H),1.79-1.83(m,4H),2.52-2.58(m,1H),2.63-2.69(m,1H),3.03-3.15(m,2H),3.62-3.68(m,2H),3.74(s,3H),7.38(s,1H)。
Example 3: synthesis of 4- (dicyclohexylphosphino) -N, N-diphenyl-1-methyl-1H-pyrazole-5-carboxamide
1-methylpyrazole (1.66 ml, 20.0 mmol) was dissolved in freshly distilled tetrahydrofuran (100 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (20.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was cooled to-78 ℃ and N, N-diphenylcarbamoyl chloride (4.17 g, 18.0 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated mixture was applied to a silica gel column and then eluted with ethyl acetate/hexane. The eluate was concentrated to evaporate, recrystallized from ethanol, and isolated as a pale yellow solid, which was dried under vacuum to give 1-methyl-N, N-diphenyl-1H-pyrazole-5-carboxamide (2.79 g, 56% yield). 1 H NMR(400MHz,CDCl 3 )δ4.16(s,3H),5.65-5.66(m,1H),7.20-7.30(m,7H),7.35-7.39(m,4H)。
1-methyl-N, N-diphenyl-1H-pyrazole-5-carboxamide (2.21 g, 8.0 mmol) was dissolved in anhydrous dimethylformamide (20 ml). N-bromosuccinimide (1.42 g, 8.0 mmol) was added at room temperature, and the reaction mixture was stirred at 80 ℃ for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Mixing after concentrationThe material was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was recrystallized from ethanol, isolated as a light brown solid and dried under vacuum to give 4-bromo-1-methyl-N, N-diphenyl-1H-pyrazole-5-carboxamide (2.56 g, 90% yield). 1 H NMR(400MHz,CDCl 3 )δ4.02(s,3H),7.21-7.34(m,11H)。
4-bromo-1-methyl-N, N-diphenyl-1H-pyrazole-5-carboxamide (1.07 g, 3.0 mmol) was dissolved in freshly distilled tetrahydrofuran (20 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.3 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodicyclohexylphosphine (0.66 ml, 3.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a degassed ethanol/water (2. The solid product was then collected by filtration and washed with a degassed ethanol/water mixture. The solid product was dried under vacuum to give 4- (dicyclohexylphosphino) -N, N-diphenyl-1-methyl-1H-pyrazole-5-carboxamide cat3 (0.81 g, 57% yield). 1 H NMR(400MHz,CDCl 3 )δ0.94-1.34(m,10H),1.52-1.99(m,12H),3.99(s,3H),7.00-7.51(m,11H)。
Example 4: synthesis of 4- (dicyclohexylphosphine) -N, N, 1-triisopropyl-1H-pyrazole-5-carboxamide
1-isopropyl-1H-pyrazole (2.30 mL, 20.0 mmol) was dissolved in freshly distilled tetrahydrofuran (100 mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (20.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was cooled to-78 ℃ and N, N-diisopropylcarbamoyl chloride (2.94 g, 18.0 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated mixture was extracted with dichloromethaneThe organic layer was diluted with an alkane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a short silica gel column and eluted with an ethyl acetate/hexane mixture. The eluate was concentrated and evaporated to yield N, 1-triisopropyl-1H-pyrazole-5-carboxamide as an orange solid (3.20 g, 75% yield). 1 H NMR(400MHz,CDCl 3 )δ1.04-1.45(m,12H),1.48-1.50(m,6H),3.45-3.61(m,1H),3.91-4.07(m,1H),4.56-4.66(m,1H),6.15(d,J＝1.8Hz,1H),7.46(d,J＝1.6Hz,1H)。
N, 1-triisopropyl-1H-pyrazole-5-carboxamide (2.37 g, 10.0 mmol) was dissolved in anhydrous dimethylformamide (20 ml). N-bromosuccinimide (1.78 g, 10.0 mmol) was added at room temperature, and the reaction mixture was stirred at 80 ℃ for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a short silica gel column and eluted with an ethyl acetate/hexane mixture. The eluate was concentrated and evaporated to give 4-bromo-N, 1-triisopropyl-1H-pyrazole-5-carboxamide as a pale yellow liquid (2.70 g, 86% yield). 1 H NMR(400MHz,CDCl 3 )δ1.07(d,J＝6.7Hz,3H),1.25(d,J＝6.6Hz,3H),1.42-1.44(m,6H),1.48-1.51(m,6H),3.45-3.55(m,1H),3.64-3.74(m,1H),4.27-4.37(m,1H),7.37(s,1H)。
4-bromo-N, 1-triisopropyl-1H-pyrazole-5-carboxamide (0.95 g, 3.0 mmol) was dissolved in freshly distilled tetrahydrofuran (20 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture with a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodicyclohexylphosphine (0.66 ml, 3.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a degassed methanol/water (2. The solid product is then collected by filtration and degassed with methanolThe/water mixture is washed. The white solid product was dried under vacuum to give 4- (dicyclohexylphosphine) -N, 1-triisopropyl-1H-pyrazole-5-carboxamide cat4 (0.50 g, 38% yield). 1 H NMR(400MHz,CD 2 Cl 2 )δ1.11-1.82(m,40H),3.43-3.60(m,1H),3.63-3.77(m,1H),4.26-4.44(m,1H),7.46(s,1H)。
Example 5: synthesis of 4- (dicyclohexylphosphine) -1-isopropyl-1H-pyrazol-5-yl) (morpholine) methanone
1-isopropyl-1H-pyrazole (2.30 mL, 20.0 mmol) was dissolved in freshly distilled tetrahydrofuran (100 mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (20.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was cooled to-78 ℃ and morpholine-4-carbonyl chloride (2.33 ml, 20.0 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a short silica gel column and eluted with an ethyl acetate/hexane mixture. Concentration of the eluent to evaporation gave (1-isopropyl-1H-pyrazol-5-yl) (morpholine) methanone (2.69 g, 60% yield) as a yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ1.50(d,J＝6.6Hz,6H),3.49-3.85(m,8H),4.71-4.78(m,1H),6.23(d,J＝1.8Hz,1H),7.49(d,J＝1.6Hz,1H)。
(1-isopropyl-1H-pyrazol-5-yl) (morpholine) methanone (5.58 g, 25.0 mmol) was dissolved in anhydrous dimethylformamide (20 ml). N-bromosuccinimide (4.45 g, 25.0 mmol) was added at room temperature, and the reaction mixture was stirred at 80 ℃ for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a short silica gel column and eluted with an ethyl acetate/hexane mixture. Will be provided withAfter the eluate was concentrated and evaporated, hexane was added to the concentrated mixture to wash. The white solid was then filtered and dried in vacuo to give (4-bromo-1-isopropyl-1H-pyrazol-5-yl) (morpholine) methanone (6.50 g, 86% yield). 1 H NMR(400MHz,CDCl 3 )δ1.38(d,J＝6.6Hz,3H),1.48(d,J＝6.5Hz,3H),3.23-3.29(m,1H),3.43-3.50(m,1H),3.53-3.59(m,1H),3.70-3.82(m,5H),4.46-4.56(m,1H),7.42(s,1H)。
(4-bromo-1-isopropyl-1H-pyrazol-5-yl) (morpholin) methanone (0.90 g, 3.0 mmol) was dissolved in freshly distilled tetrahydrofuran (20 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodicyclohexylphosphine (0.66 ml, 3.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the concentrated mixture was washed with cold degassed methanol, and the white solid product was collected by filtration and dried under vacuum to give 4- (dicyclohexylphosphine) -1-isopropyl-1H-pyrazol-5-yl) (morpholine) methanone cat5 (0.73 g, 58% yield). 1 H NMR(400MHz,CDCl 3 )δ0.81-1.38(m,12H),1.44(d,J＝6.6Hz,3H),1.52(d,J＝6.6Hz,3H),1.64-1.84(m,9H),2.02-2.11(m,1H),3.13-3.22(m,1H),3.40-3.53(m,2H),3.71-3.89(m,5H),4.45-4.51(m,1H),7.46(s,1H)。
In addition, the 4- (disubstituted phosphino) -N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamidophosphine ligands shown in Table 1 below can be prepared by methods described with reference to the following reaction schemes.
TABLE 1
Example 6: use of phosphine ligands of pyrazole-amide frameworks for palladium-catalysed Suzuki-Miyaura reactions of (hetero) aryl chlorides and (hetero) arylboronic esters in Suzuki-Miyaura reactions of (hetero) aryl chlorides with (hetero) aryl boronates.
The structures of several catalysts of the phosphine ligand of pyrazole-amide skeleton in the embodiment of the invention are shown as the following formula cat 1-5:
8.1 Suzuki-Miyaura catalysis of highly sterically hindered (hetero) aryl chlorides and (hetero) arylboronic acid esters with phosphine ligands of the pyrazole-amide skeleton and other phosphine ligands
Comparison in cross-coupling reaction:
procedure when the amount of palladium equals 2.0 mol% of the tall oil palladium acetate (0.0022 g, 0.010 mmol), phosphine ligand (palladium: phosphine ligand ratio 2.0 mol%: 4.0 mol%), potassium phosphate (1.5 mmol), and a magnetic stir bar fitted with a polytetrafluoroethylene coating were placed in a 20 ml Schlenk tube. After purging nitrogen 3 times, 2-chloro-1, 3-xylene (0.5 mmol), 2-methylphenylboronic acid pinacol ester (0.75 mmol) and freshly distilled 1, 4-dioxane (1.5 ml) were added under nitrogen. The Schlenk tube was then stirred at room temperature for 1 minute, and then the Schlenk tube was reacted at 110 ℃ for 10 to 30 minutes. The reaction tube was then cooled to room temperature, and the reaction was stopped. Ethyl acetate (8.0 ml), dodecane (113.0 μ l) and water (4.0 ml) were then added to the system, and the extracted organic layer was subjected to gas chromatography and examined to determine the yield of the coupled product.
Procedure when palladium was used in an amount equal to 0.05 mol% of the tall oil palladium acetate (0.0045 g, 0.020 mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 8 mol%) and a magnetic stir bar equipped with a polytetrafluoroethylene coating were placed in a 20 ml Schlenk tube. After 3 nitrogen purges, freshly distilled 1, 4-dioxane (8 ml) was added under nitrogen and stirred at room temperature until all the solid had dissolved. Potassium phosphate (1.5 mmol) and a magnetic stir bar fitted with a Teflon coating were placed in another 20 ml Schlenk tube and the system replaced with nitrogen blanket. 2-chloro-1, 3-xylene (0.5 mmol), 2-methylphenylboronic acid pinacol ester (0.75 mmol), palladium metal complex solution (0.1 ml) and freshly distilled 1, 4-dioxane (1.4 ml) were added under nitrogen. The Schlenk tube was then stirred at room temperature for 1 minute, and then the Schlenk tube was allowed to react at 110 ℃ for 30 minutes. The reaction tube was then cooled to room temperature, and the reaction was stopped. Ethyl acetate (8.0 ml), dodecane (113.0 μ l) and water (4.0 ml) were then added to the system, and the extracted organic layer was analyzed by gas chromatography and checked to determine the yield of the coupled product.
The reaction formula of the above reaction is as follows:
wherein, in the Suzuki-Miyaura cross-coupling reaction, the phosphine ligand and the yield of the catalyst are shown in the following table 2.
TABLE 2 [a]
a Reaction conditions 2-chloro-1, 3-xylene (0.50 mmol), 2-methylphenylboronic acid pinacol ester (0.75 mmol), palladium acetate (0.05-2 mol%), phosphine ligand (0.1-4 mol%), potassium phosphate (1.50 mmol) and 1, 4-dioxane (1.50 ml) were reacted at 110 ℃ for 10-30 minutes. b Corrected GC yield using dodecane as an internal standard.
As can be seen from table 2, the phosphine ligands of the pyrazole-amide skeletons can show good catalytic performance in the suzuki-miyaura cross-coupling reaction of the palladium-catalyzed high-steric hindrance (hetero) aryl chloride and (hetero) aryl borate, and have better catalytic efficiency than other commercially available ligands.
6.2 high steric hindrance Suzuki-Miyaura cross-coupling reaction catalyzed by phosphine ligand of pyrazole-amide framework in the presence of different substrates
Palladium acetate (0.0018 g, 0.0080 mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 8 mol%) and a magnetic stir bar equipped with a teflon coating were placed in a 10ml Schlenk tube. After 3 nitrogen purges, freshly distilled tetrahydrofuran (4 ml) was added under nitrogen and stirred at room temperature until all solids were dissolved. Aryl chloride (0.2 mmol if solid), arylboronic acid ester (0.3-0.4 mmol if solid), and potassium phosphate (0.6 mmol) and a teflon-coated magnetic stir bar were placed in another 20 ml Schlenk tube and the system replaced with a nitrogen blanket. Aryl chloride (0.2 mmol if liquid), arylboronic acid ester (0.3-0.4 mmol if liquid), corresponding amounts of palladium metal complex solution and freshly distilled tetrahydrofuran (final solvent volume: 0.6 mL) were added with nitrogen. Then the Schlenk tube was stirred at room temperature for 1 minute, and then the Schlenk tube was reacted at 110 ℃ for 1 to 24 hours, the reaction formula is shown below. After the reaction was completed, the reaction tube was cooled to room temperature, and the reaction was stopped. Ethyl acetate (8.0 mL) and water (4.0 mL) were then added to the system, and the extracted organic layer was subjected to gas chromatography. After which about 10mL of ethyl acetate are added three to four times each for extraction and the organic phases are combined. The organic phase is concentrated under reduced pressure and purified by column chromatography on silica gel to give the cross-coupled product.
Wherein, in the suzuki-miyaura cross-coupling reaction of the palladium-catalyzed high-steric-hindrance (hetero) aryl chloride and (hetero) aryl borate, the dosage of palladium, the catalyst phosphine ligand and the yield are shown in the following table 3.
TABLE 3 a
[a] Reaction conditions aryl chloride (0.20 mmol), arylboronic acid ester (0.30 mmol), pd (OAc) 2 Cat1=1, potassium phosphate (0.60 mmol) and tetrahydrofuran (0.60 ml) were stirred at 110 ℃ under nitrogen atmosphere. [b] Pd(OAc) 2 :cat1＝1:4. [c] An arylboronic acid ester (0.40 mmol) was used.
As can be seen from table 3 above, when the phosphine ligand of pyrazole-amide skeleton of the embodiment of the present invention is used in the suzuki-miyaura cross-coupling reaction of the first highly hindered (hetero) aryl chloride and (hetero) arylboronic acid ester, ortho-tri-substituted and very challenging ortho-tetra-substituted biaryl products can be obtained under the condition of ensuring the separation yield, and the palladium usage (mol%) is greatly reduced, and between 0.005 and 0.6, the separation yield reaches 99%.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. A phosphine ligand with a pyrazole-amide skeleton is characterized by having a structural formula shown as follows:
2. Phosphine ligand of pyrazole-amide framework according to claim 1, characterized in that said R is 1 、R 2 Independently is one of C1-C10 alkyl, C3-C10 cycloalkyl, phenyl and pyridyl; the R is 1 -R 2 Or one of C3-C10 cycloalkyl, morpholine, carbazole, benzoxazine, phenothiazine, iminostilbene and iminodibenzyl; the R is 3 Is one of C1-C10 alkyl, C3-C10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle alkyl and phenyl; the R is 4 Is one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl; the R is 5 、R 6 Is independently one of phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl.
3. Phosphine ligand of pyrazole-amide framework according to claim 1, characterized in that said R is 1 And R 2 The C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, and the C3-C10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C7-C10 cycloalkyl groups;
said R is 3 Wherein the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl, the C3-C10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl, the oxirane ring includes tetrahydrofuran, the oxirane group includes glycidyl, the alkoxyalkyl group includes methoxymethyl, and the oxacycloalkyl group includes tetrahydrofurylmethyl;
said R is 4 The C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, and the C1-C10 alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy groups.
4. A preparation method of a phosphine ligand with a pyrazole-amide skeleton is characterized by comprising the following steps:
preparing an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
reacting the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate with N-bromosuccinimide to obtain a 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate;
reacting the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate, N-butyllithium and disubstituted phosphine chloride to obtain the phosphine ligand with a pyrazole-amide skeleton.
5. The process for preparing a phosphine ligand of pyrazole-amide skeleton according to claim 4, wherein the preparation of the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate comprises the steps of:
dissolving 1-alkyl-1H-pyrazole-5-carboxylic acid in anhydrous chloroform, adding oxalyl chloride at room temperature, then dropwise adding dimethylformamide, and heating and refluxing the reaction solution, wherein the molar ratio of the 1-alkyl-1H-pyrazole-5-carboxylic acid to the oxalyl chloride to the N, N-disubstituted amine is 1.0;
after the reaction liquid is decompressed and concentrated, the concentrated mixture is dissolved in anhydrous chloroform and cooled to 0 ℃, N-disubstituted amine is added at 0 ℃, and then stirring is carried out at 70 ℃;
after the reaction is finished, adding water into the system, adding ethyl acetate for extraction and separation, then adding ethyl acetate into the water phase for extraction for a plurality of times, combining and concentrating the organic phases, and purifying by column chromatography to obtain the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate.
6. The process for preparing a phosphine ligand of pyrazole-amide skeleton according to claim 4, wherein the preparation of the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate comprises the steps of:
dissolving 1-alkyl pyrazole in tetrahydrofuran, dropwise adding N-butyl lithium at the temperature of-75 to-80 ℃, uniformly stirring for 30 minutes at room temperature, then adding N, N-disubstituted carbamoyl chloride at the temperature of-75 to-80 ℃, and then heating the reaction mixture to room temperature and stirring for 1 hour, wherein the molar ratio of the 1-alkyl pyrazole, the N-butyl lithium and the N, N-disubstituted carbamoyl chloride is (1.0-1.1) to 1.0;
after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine;
the organic layer was dried over anhydrous sodium sulfate, the organic phase was concentrated, the concentrated mixture was loaded on a silica gel column, and then eluted with ethyl acetate/hexane, and the eluate was concentrated and evaporated to give an N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate.
7. The method for producing a phosphine ligand of pyrazole-amide skeleton according to claim 4, wherein the step of reacting the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate with N-bromosuccinimide to obtain a 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate comprises:
dissolving the N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate in anhydrous dimethylformamide, adding N-bromosuccinimide at room temperature, and stirring the reaction mixture at 80 ℃ for 1 hour, wherein the molar ratio of N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide to N-bromosuccinimide is 1.0;
after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was diluted with dichloromethane and the organic layer was washed with water and brine;
the organic layer was dried over anhydrous sodium sulfate, concentrated, and dried under vacuum to give 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate.
8. The method for producing a phosphine ligand of pyrazole-amide skeleton according to claim 4, wherein the step of reacting the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate, N-butyllithium and disubstituted phosphine chloride to obtain a phosphine ligand of pyrazole-amide skeleton comprises:
dissolving the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide intermediate in tetrahydrofuran, adding N-butyllithium at the temperature of-75 to-80 ℃, uniformly stirring for 20 to 30 minutes, then adding disubstituted phosphine chloride, and reacting at room temperature for 2 to 24 hours, wherein the molar ratio of the 4-bromo-N, N-disubstituted-1-alkyl-1H-pyrazole-5-carboxamide to N-butyllithium to disubstituted chlorophosphine is 1.0 (1.0-1.1) to 1.0-1.1;
and after the reaction is finished, carrying out reduced pressure concentration on the reaction liquid, adding a degassing solvent into the concentrated mixture for washing, filtering and collecting a solid product, and then carrying out vacuum drying to obtain the phosphine ligand with the pyrazole-amide skeleton.
9. Use of phosphine ligands of pyrazole-amide skeleton according to any of claims 1 to 3 as synergists for transition metal catalysts in cross-coupling reactions.
10. Use according to claim 9, wherein the cross-coupling reaction comprises suzuki coupling reaction, panda coupling reaction, root-shore coupling reaction, sabina coupling reaction, boron-based coupling reaction and cyanation reaction.
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Citations (5)
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| US3843679A (en) * | 1972-04-21 | 1974-10-22 | Bayer Ag | O-alkyl-o-(1,3-disubstituted-pyrazol(5)yl)-(thiono)-phosphoric(phosphonic)acid esters |
| WO2005082917A1 (en) * | 2004-02-26 | 2005-09-09 | Bayer Cropscience S.A. | 4-phosphorylpyrazole derivatives for pesticidal use |
| CN107445991A (en) * | 2016-06-01 | 2017-12-08 | 香港理工大学深圳研究院 | A kind of Phosphine ligands of indoles skeleton and its preparation method and application |
| CN113402553A (en) * | 2021-06-09 | 2021-09-17 | 香港理工大学深圳研究院 | 2-alkyl-indole skeleton phosphine ligand and preparation method and application thereof |
| CN114907404A (en) * | 2021-02-09 | 2022-08-16 | 香港理工大学深圳研究院 | 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3843679A (en) * | 1972-04-21 | 1974-10-22 | Bayer Ag | O-alkyl-o-(1,3-disubstituted-pyrazol(5)yl)-(thiono)-phosphoric(phosphonic)acid esters |
| WO2005082917A1 (en) * | 2004-02-26 | 2005-09-09 | Bayer Cropscience S.A. | 4-phosphorylpyrazole derivatives for pesticidal use |
| CN107445991A (en) * | 2016-06-01 | 2017-12-08 | 香港理工大学深圳研究院 | A kind of Phosphine ligands of indoles skeleton and its preparation method and application |
| CN114907404A (en) * | 2021-02-09 | 2022-08-16 | 香港理工大学深圳研究院 | 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof |
| CN113402553A (en) * | 2021-06-09 | 2021-09-17 | 香港理工大学深圳研究院 | 2-alkyl-indole skeleton phosphine ligand and preparation method and application thereof |
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