CN111377964B - Pyrazole-triazole phosphine compound and application thereof - Google Patents
Pyrazole-triazole phosphine compound and application thereof Download PDFInfo
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- CN111377964B CN111377964B CN202010001686.1A CN202010001686A CN111377964B CN 111377964 B CN111377964 B CN 111377964B CN 202010001686 A CN202010001686 A CN 202010001686A CN 111377964 B CN111377964 B CN 111377964B
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- -1 Pyrazole-triazole phosphine compound Chemical class 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 238000005859 coupling reaction Methods 0.000 claims abstract description 16
- 150000003254 radicals Chemical class 0.000 claims abstract description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 332
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 261
- 229910052757 nitrogen Inorganic materials 0.000 claims description 159
- 239000002904 solvent Substances 0.000 claims description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 84
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 75
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 44
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 44
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 40
- 239000003054 catalyst Substances 0.000 claims description 39
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- 230000035484 reaction time Effects 0.000 claims description 27
- 229910052723 transition metal Inorganic materials 0.000 claims description 25
- 150000003624 transition metals Chemical class 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 23
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 23
- 239000003513 alkali Substances 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 20
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 230000001681 protective effect Effects 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 150000003457 sulfones Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 7
- 125000003158 alcohol group Chemical group 0.000 claims 3
- 239000003849 aromatic solvent Substances 0.000 claims 2
- 125000001033 ether group Chemical group 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 230000008878 coupling Effects 0.000 abstract description 4
- 238000010168 coupling process Methods 0.000 abstract description 4
- 150000001412 amines Chemical class 0.000 abstract description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract description 3
- 150000004820 halides Chemical class 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- 239000003446 ligand Substances 0.000 description 52
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 239000007791 liquid phase Substances 0.000 description 38
- 238000001514 detection method Methods 0.000 description 35
- 238000004440 column chromatography Methods 0.000 description 34
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 33
- 239000003208 petroleum Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- 239000002994 raw material Substances 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000010438 heat treatment Methods 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- 238000006467 substitution reaction Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 18
- 238000007036 catalytic synthesis reaction Methods 0.000 description 15
- 238000002156 mixing Methods 0.000 description 13
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 230000000171 quenching effect Effects 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000005658 halogenation reaction Methods 0.000 description 8
- DYFFAVRFJWYYQO-UHFFFAOYSA-N n-methyl-n-phenylaniline Chemical compound C=1C=CC=CC=1N(C)C1=CC=CC=C1 DYFFAVRFJWYYQO-UHFFFAOYSA-N 0.000 description 8
- 125000001425 triazolyl group Chemical group 0.000 description 8
- BYAJHZYXPBREEK-UHFFFAOYSA-N 2-bromo-1,3-diphenylpropane-1,3-dione Chemical compound C=1C=CC=CC=1C(=O)C(Br)C(=O)C1=CC=CC=C1 BYAJHZYXPBREEK-UHFFFAOYSA-N 0.000 description 7
- MDUSUFIKBUMDTJ-UHFFFAOYSA-N sodium;1h-1,2,4-triazole Chemical compound [Na].C=1N=CNN=1 MDUSUFIKBUMDTJ-UHFFFAOYSA-N 0.000 description 7
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical compound C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 5
- SNHZCMQKWIMSSK-UHFFFAOYSA-N n-(2-methoxyphenyl)-2,6-dimethylaniline Chemical group COC1=CC=CC=C1NC1=C(C)C=CC=C1C SNHZCMQKWIMSSK-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000005731 phosphitylation reaction Methods 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- SQIUEWNROMQRQY-UHFFFAOYSA-N 2,6-dimethyl-n-phenylaniline Chemical compound CC1=CC=CC(C)=C1NC1=CC=CC=C1 SQIUEWNROMQRQY-UHFFFAOYSA-N 0.000 description 4
- FHQRDEDZJIFJAL-UHFFFAOYSA-N 4-phenylmorpholine Chemical compound C1COCCN1C1=CC=CC=C1 FHQRDEDZJIFJAL-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- ZVSKZLHKADLHSD-UHFFFAOYSA-N benzanilide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=CC=C1 ZVSKZLHKADLHSD-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 3
- OLZIFTWXJDRFTK-UHFFFAOYSA-N 2,6-dimethyl-n-(2-nitrophenyl)aniline Chemical compound CC1=CC=CC(C)=C1NC1=CC=CC=C1[N+]([O-])=O OLZIFTWXJDRFTK-UHFFFAOYSA-N 0.000 description 3
- VZARMICIYMJKKP-UHFFFAOYSA-N 4-(3-methoxyphenyl)morpholine Chemical compound COC1=CC=CC(N2CCOCC2)=C1 VZARMICIYMJKKP-UHFFFAOYSA-N 0.000 description 3
- IAJDSUYFELYZCS-UHFFFAOYSA-N 4-(4-nitrophenyl)morpholine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCOCC1 IAJDSUYFELYZCS-UHFFFAOYSA-N 0.000 description 3
- VCFXHOIHPGPHMF-UHFFFAOYSA-N 4-naphthalen-1-ylmorpholine Chemical compound C1COCCN1C1=CC=CC2=CC=CC=C12 VCFXHOIHPGPHMF-UHFFFAOYSA-N 0.000 description 3
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- LXZGVFCKZRHKMU-UHFFFAOYSA-N n-benzyl-n-methylaniline Chemical compound C=1C=CC=CC=1N(C)CC1=CC=CC=C1 LXZGVFCKZRHKMU-UHFFFAOYSA-N 0.000 description 3
- VKEFCFUJDRIEBB-UHFFFAOYSA-N n-methyl-2-nitro-n-phenylaniline Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C)C1=CC=CC=C1 VKEFCFUJDRIEBB-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000004576 sand Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 2
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 2
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 2
- JYNABQRMIKWGTK-UHFFFAOYSA-N 4-methoxy-n-methyl-n-phenylaniline Chemical compound C1=CC(OC)=CC=C1N(C)C1=CC=CC=C1 JYNABQRMIKWGTK-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 238000007341 Heck reaction Methods 0.000 description 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- 238000006411 Negishi coupling reaction Methods 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000006619 Stille reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
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- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
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- 239000012498 ultrapure water Substances 0.000 description 2
- RUAFPCMISXUGHL-UHFFFAOYSA-N 1,1'-biphenyl;phosphane Chemical compound P.C1=CC=CC=C1C1=CC=CC=C1 RUAFPCMISXUGHL-UHFFFAOYSA-N 0.000 description 1
- OMNWKPZIFZJANV-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1C1=CC=C(Cl)C=C1 OMNWKPZIFZJANV-UHFFFAOYSA-N 0.000 description 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- ZDFBKZUDCQQKAC-UHFFFAOYSA-N 1-bromo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1 ZDFBKZUDCQQKAC-UHFFFAOYSA-N 0.000 description 1
- DLKQHBOKULLWDQ-UHFFFAOYSA-N 1-bromonaphthalene Chemical compound C1=CC=C2C(Br)=CC=CC2=C1 DLKQHBOKULLWDQ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- FNEXGSTVMVVQOB-UHFFFAOYSA-N COC1=CC=C(C=C1)C1=C(N(C2=CC=CC=C2)C)C=CC=C1 Chemical compound COC1=CC=C(C=C1)C1=C(N(C2=CC=CC=C2)C)C=CC=C1 FNEXGSTVMVVQOB-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- NZZIMKJIVMHWJC-UHFFFAOYSA-N dibenzoylmethane Chemical compound C=1C=CC=CC=1C(=O)CC(=O)C1=CC=CC=C1 NZZIMKJIVMHWJC-UHFFFAOYSA-N 0.000 description 1
- WDOKISJWRVNYNS-UHFFFAOYSA-N dicyclohexylphosphanium;chloride Chemical compound Cl.C1CCCCC1PC1CCCCC1 WDOKISJWRVNYNS-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- DOWCWUCBOQRQJE-UHFFFAOYSA-N ditert-butylphosphane;hydrochloride Chemical compound Cl.CC(C)(C)PC(C)(C)C DOWCWUCBOQRQJE-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
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- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 1
Images
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- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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Abstract
The invention discloses a pyrazole triazole phosphine compound and application thereof. The invention discloses a compound shown as a formula I, wherein R1Is hydrogen,C1‑C6Alkyl or phenyl; r2And R3Is phenyl; r4And R5Independently is C1‑C6Alkyl radical, C3‑C8Cycloalkyl or phenyl. The pyrazole bis-triazole phosphine compound has stable property, excellent catalytic effect and high selectivity, and can be applied to catalytic coupling of amine, boric acid compounds and halides.
Description
Technical Field
The invention relates to a pyrazole triazole phosphine compound and application thereof.
Background
In organic synthesis reactions, the reaction used to form the C-N, C-C, C-S, C-B bond is a coupling reaction. And simple small molecules can be converted into molecules with complex structures by utilizing the reactions. Transition metal catalyzed coupling reactions are one of the effective means for achieving this type of conversion. The coupling reaction mainly comprises a Heck reaction, a Suzuki reaction, a Stille reaction, a Negishi reaction, a Buchwald-Hartwig reaction and the like. These coupling reactions have a very wide range of applications in the synthesis of polymers, functional materials, natural organic products, drugs and intermediates related to pharmaceuticals and pesticides, and bioactive compounds.
Researches show that in the process of catalyzing the coupling reaction, the addition of the ligand can effectively reduce the usage amount of the catalyst and improve the reaction rate and the selectivity of the reaction. At present, the application range is wider than that of Buchwald ligands, biphenyl monophosphine ligands and general dialkyl phosphine ligands. The ligand increases the stability of the phosphine ligand due to the steric hindrance of the aryl below, and is not easy to be oxidized by air. However, since Buchwald ligands cannot be produced on a large scale, Singer et al prepare a binuclear ligand generated from a heterocycle by a simple direct condensation reaction, and prepare a Bippyphos ligand by continuous modification and transformation.
Disclosure of Invention
The invention aims to overcome the defect that the existing ligand applied to C-N and C-C coupling is single in the field, and provides a pyrazole triazole phosphine compound and application thereof. The pyrazole bis-triazole phosphine compound has stable property, good catalytic effect and high selectivity, and can be applied to catalytic coupling of amine, boric acid compounds and halides.
The present invention solves the above problems by the following means.
The invention provides a compound shown as a formula I,
wherein R is1Is hydrogen, C1-C6Alkyl or phenyl;
R2and R3Is phenyl;
R4and R5Independently is C1-C6Alkyl radical, C3-C8Cycloalkyl or phenyl.
In certain embodiments, when said R is1Is C1-C6When alkyl, said C1-C6Alkyl is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, for example the ethyl radical.
In certain embodiments, when said R is4And R5Independently is C1-C6When alkyl, said C1-C6Alkyl is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and tert-butyl radicals are further exemplified.
In certain embodiments, when said R is4And R5Independently is C3-C8When there is a cycloalkyl group, said C3-C8Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, for example cyclohexyl.
In certain embodiments, said R is1Is C1-C6An alkyl group.
In certain embodiments, said R is4And R5Independently is C1-C6Alkyl or C3-C8A cycloalkyl group.
In certain embodiments, said R is4And R5Identical or different, for example identical.
In some embodimentsIn the formula I, the compound is
The invention provides a catalyst composition, which comprises the compound shown in the formula I and a transition metal catalyst.
In certain embodiments, the catalyst composition consists of the compound of formula I and a transition metal catalyst.
In certain embodiments, all or a portion of the compound of formula I and all or a portion of the transition metal catalyst are present in the form of a complex.
In certain embodiments, the transition metal catalyst is Pd (dba)2One or more of palladium chloride and palladium acetate, preferably Pd (dba)2And/or palladium chloride.
In certain embodiments, the catalyst composition comprises the compound of formula I and the transition metal catalyst in a molar ratio of 1:1:10:1, such as 1:1 to 2.5:1, for example, 1.79:1, 1.86:1, 1.93:1, 2.07:1, or 2.1: 1.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: under the action of alkali in a solvent under the protection gas, carrying out a phosphido reaction on a compound shown as a formula II and a compound shown as a formula III to obtain a compound shown as a formula I,
wherein R is1、R2、R3、R4And R5As defined above; x is halogen.
In certain embodiments, X is fluorine, chlorine, bromine, or iodine, e.g., chlorine.
In the phosphine reaction, the protective gas can be a protective gas conventional in the reaction in the field, and the invention particularly preferably adopts nitrogen or argon, such as nitrogen.
In the phosphido reaction, the solvent can be a solvent which is conventional in the reaction in the field, and the invention particularly preferably adopts an ether solvent, such as tetrahydrofuran.
In the phosphido reaction, the molar concentration of the compound shown in the formula II in the solvent can be the molar concentration conventional in the reaction in the field, and the invention is particularly preferably 0.1mol/L-1mol/L, such as 0.2mol/L-0.4mol/L, and further such as 0.228 mol/L.
In the phosphitylation reaction, the base may be a base conventional in the art, and n-butyllithium is particularly preferred in the present invention.
In the phosphitylation reaction, the molar ratio of the base to the compound of formula II may be a molar ratio which is conventional in the art for such reactions, and is particularly preferably 1:1 to 3:1, such as 1:1 to 2:1, and further such as 1.5:1 in the present invention.
In the phosphido reaction, the molar ratio of the compound shown in the formula III to the compound shown in the formula II can be the molar ratio which is conventional in the reaction in the field, and the invention particularly preferably adopts the molar ratio of 1:1-3:1, such as 1:1-2:1, and further such as 1.5:1 and 1.45: 1.
In the phosphido reaction, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction of the type in the field, and room temperature is particularly preferred in the present invention.
In the phosphitylation reaction, the reaction time of the reaction can be the reaction time conventional in the reaction of the type in the field, and the reaction time is particularly preferably 10h to 15 h.
In the phosphitylation reaction, the reaction is preferably carried out under anhydrous conditions.
In the phosphine generation reaction, after the reaction is finished, the method can further comprise a post-treatment step. The post-treatment steps may include quenching reactions, extraction, drying, concentration and purification. The reagent used for quenching the reaction may be water. The reagent used for the extraction may be ethyl acetate. The reagent used for drying can be anhydrous sodium sulfate. The purification mode can be column chromatography (preferably column chromatography under the protection of nitrogen). The reagents used for the column chromatography may be petroleum ether and ethyl acetate (volume ratio is preferably 15: 1). The diameter-to-height ratio of the column used for column chromatography may be 3: 19.
In the phosphitylation reaction, the reaction may include the steps of: and under the protective gas, mixing the solvent, the alkali and the compound shown as the formula II for reaction, and mixing the mixture with the compound shown as the formula III for reaction.
The preparation method of the compound shown in the formula I can further comprise the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula IV and a compound shown as a formula V to obtain a compound shown as a formula II,
wherein R is1、R2And R3As defined above; x1Is halogen.
In certain embodiments, X1Is fluorine, chlorine, bromine or iodine, for example iodine.
In the substitution reaction, the solvent can be a solvent which is conventional in the reaction of the type in the field, and the present invention particularly preferably refers to an amide solvent such as N-methylpyrrolidone.
In the substitution reaction, the molar concentration of the compound shown in the formula IV in the solvent can be the molar concentration which is conventional in the reactions in the field, and the invention particularly preferably adopts the molar concentration of 0.1mol/L-1mol/L, such as 0.5mol/L-0.8mol/L, and further such as 0.6 mol/L.
In the substitution reaction, the base may be a base conventional in the art, and a carbonate such as potassium carbonate is particularly preferred in the present invention.
The molar ratio of the base to the compound of formula IV in the substitution reaction may be that which is conventional in such reactions in the art, and the present invention is particularly preferably from 1:1 to 4:1, such as from 2:1 to 3:1, and further such as 2.5: 1.
In the substitution reaction, the molar ratio of the compound shown in the formula IV and the compound shown in the formula V can be the molar ratio which is conventional in the reaction in the field, and the invention particularly preferably adopts the molar ratio of 1:1 to 3:1, such as 1:1 to 1.5:1, and further such as 1.26: 1.
In the substitution reaction, the reaction temperature of the reaction can be a reaction temperature conventional in the reaction of this type in the art, and room temperature is particularly preferred in the present invention.
In the substitution reaction, the reaction time of the reaction can be the reaction time conventional in the reaction of the type in the field, and the reaction time is particularly preferably 2h to 5h, for example 3 h.
In the substitution reaction, after the reaction is finished, the method can further comprise a post-treatment step. The post-treatment step may include cooling, quenching the reaction, filtering, washing, recrystallization, and filtering. The reagent used for quenching the reaction may be water. The agent used for washing may be water. The reagent used for recrystallization may be toluene.
In the substitution reaction, the reaction may include the steps of: mixing the solvent, the alkali and the compound shown in the formula IV for reaction, and mixing the mixture with the compound shown in the formula V for reaction.
The preparation method of the compound shown in the formula I can further comprise the following steps:
step 1: under protective gas, carrying out triazolyl substitution reaction on a compound shown as a formula VII and 1,2, 4-triazole sodium salt shown as a formula VI in a solvent to obtain a compound shown as a formula VI;
step 2: in a solvent, under the action of acid, carrying out cyclization reaction on a compound shown as a formula VI and hydrazine hydrate as shown in the specification to obtain a compound shown as a formula IV;
wherein R is2And R3As defined above; x2Is halogen.
In certain embodiments, X2Is fluorine, chlorine, bromine or iodine, for example iodine.
In the triazolyl substitution reaction, the protective gas can be a protective gas conventional in the reaction in the field, and nitrogen or argon, such as nitrogen, is particularly preferred in the invention.
In the triazolyl substitution reaction, the solvent can be a solvent which is conventional in the reaction in the field, and the amide solvent such as N, N-dimethylformamide is particularly preferred in the invention.
In the triazolyl substitution reaction, the molar concentration of the compound shown in the formula VII in the solvent can be the molar concentration conventional in the reactions in the field, and the invention is particularly preferably 0.1mol/L-2mol/L, such as 0.5mol/L-1.5mol/L, and further such as 0.94 mol/L.
In the triazolyl substitution reaction, the molar ratio of the 1,2, 4-triazole sodium salt to the compound shown in the formula VII can be the molar ratio which is conventional in the reaction in the field, and the molar ratio is particularly preferably 1:1-3:1, such as 2: 1.
In the triazolyl substitution reaction, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction of the type in the field, and the reaction temperature is particularly preferably 30 ℃ to 50 ℃, for example 45 ℃ in the invention.
In the triazolyl substitution reaction, the reaction time of the reaction can be the reaction time conventional in the reaction of the type in the field, and the reaction time is particularly preferably 1h to 5h, for example 2 h.
In some embodiments, in the triazolyl substitution reaction, the sodium salt of 1,2, 4-triazole is mixed with a portion of the solvent, and then mixed with the compound represented by formula VII and the rest of the solvent to perform the reaction.
In the cyclization reaction, the solvent can be a solvent which is conventional in the reaction in the field, and the invention particularly preferably adopts an amide solvent, such as N, N-dimethylformamide.
In the ring formation reaction, the molar concentration of the compound shown in the formula VI in the solvent can be the molar concentration conventional in the reactions in the field, and the invention is particularly preferably 0.1mol/L-2mol/L, such as 0.5mol/L-1.5mol/L, and further such as 0.825 mol/L.
In the cyclization reaction, the molar ratio of the hydrazine hydrate to the compound shown in the formula VI can be the molar ratio which is conventional in the reaction in the field, and the invention particularly preferably adopts the molar ratio of 1:1-3:1, such as 1.5: 1.
In the cyclization reaction, the reaction temperature of the reaction can be a reaction temperature conventional in the reaction of the type in the art, and the reaction temperature is particularly preferably 30 ℃ to 50 ℃, for example 45 ℃ in the present invention.
In the ring formation reaction, the reaction time of the reaction can be the reaction time conventional in the reaction of this type in the art, and the present invention is particularly preferably from 40min to 90min, for example 75 min.
In the cyclization reaction, the reaction is preferably carried out under anhydrous conditions.
In the cyclization reaction, after the reaction is finished, the method can further comprise a post-treatment step. The post-treatment step may include cooling, quenching the reaction, cooling, filtering, washing and drying. The reagent used for quenching the reaction may be water. The reagents used for the washing may be water and n-heptane.
The preparation method of the compound shown in the formula I can further comprise the following steps: in a solvent, a compound shown as a formula VIII and X2 2Performing halogenation reaction as shown in the specification to obtain a compound shown in a formula VII,
wherein R is2、R3And X2As defined aboveAnd (5) defining.
In the halogenation reaction, the solvent can be a solvent which is conventional in the reactions of the type in the field, and the invention particularly preferably adopts an amide solvent, such as N-methylpyrrolidone.
In the halogenation reaction, the molar concentration of the compound shown in the formula VIII in the solvent can be the molar concentration which is conventional in the reactions in the field, and the invention particularly preferably adopts 0.1mol/L-2mol/L, such as 0.5mol/L-1.5mol/L, and further such as 1.1125 mol/L.
In the halogenation reaction, the X2 2And the molar ratio of the compound of formula VII may be that which is conventional for reactions of this type in the art, and is particularly preferred in the present invention to be in the range of from 1:1 to 2:1, for example 1.2: 1.
In the halogenation reaction, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction of the type in the field, and room temperature is particularly preferred in the invention.
In the halogenation reaction, the reaction takes the disappearance of the compound shown as the formula VIII detected as a reaction end point.
In the halogenation reaction, after the reaction is finished, the method can further comprise a post-treatment step. The post-treatment step may include quenching the reaction, reducing the temperature, filtering and washing. The reagent used for quenching the reaction may be water.
In the halogenation reaction, the reaction may comprise the steps of: mixing the compound shown as the formula VIII with the solvent, and then mixing with the X2 2Mixing and reacting.
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula IV and a compound shown as a formula V to obtain a compound shown as a formula II,
wherein R is1、R2、R3And X1As defined above.
The preparation method of the compound shown in the formula II has the same conditions as the above.
In certain embodiments, the methods of preparing the compound of formula II further include methods of preparing the compound of formula IV.
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps:
step 1: carrying out substitution reaction 3 shown as the following on a compound shown as a formula VII and 1,2, 4-triazole sodium salt in a solvent under protective gas to obtain a compound shown as a formula VI;
step 2: in a solvent, under the action of acid, carrying out cyclization reaction on a compound shown as a formula VI and hydrazine hydrate as shown in the specification to obtain a compound shown as a formula IV;
wherein R is2、R3And X2As defined above.
The preparation method of the compound shown in the formula IV has the same conditions as the above.
In certain embodiments, the process for preparing a compound of formula IV further comprises a process for preparing a compound of formula VII.
The invention also provides application of the compound shown in the formula I or the catalyst composition in the coupling reaction. In the application, the compound shown in the formula I can be used as a ligand. In the application, the coupling reaction can be a coupling reaction conventional in the art (such as a C-N coupling reaction, a C-C coupling reaction, a C-S coupling reaction, a C-B coupling reaction); also for example a Heck reaction, a Suzuki reaction, a Stille reaction, a Negishi reaction or a Buchwald-Hartwig reaction.
In certain embodiments, the use comprises a process for the preparation of a compound of formula IX or a process for the preparation of a compound of formula XII.
The preparation method of the compound shown in the formula IX comprises the following steps: under the action of alkali, the compound shown in the formula I and the transition metal catalyst in a solvent under the protection gas, carrying out Buchwald-Hartwig reaction shown in the specification on the compound shown in the formula X and the compound shown in the formula XI to obtain the compound shown in the formula IX,
wherein R is6And R7Independently hydrogen, by one or more R9Substituted C6-C14Aryl radical, C6-C14Aryl radicals, substituted by one or more R10Substituted C1-C6Alkyl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl or-C (═ O) R11(ii) a Or R6And R7And the above R6And R7Form a 3-to 8-membered heterocycloalkyl group with the nitrogen atom in between, or, by one or more R12Substituted 3-8 membered heterocycloalkyl; wherein, 3-8 membered heterocycloalkyl is substituted with one or more R11In the 3-to 8-membered heterocycloalkyl group of the substituted 3-to 8-membered heterocycloalkyl group, except for the above-mentioned R6And R7The rest heteroatoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of the rest heteroatoms is 0, 1,2 or 3;
R8is C6-C14Aryl, or, by one or more R13Substituted C6-C14An aryl group;
X3is halogen;
R9is C1-C6An alkyl group;
R10is C6-C10An aryl group;
R11is C6-C10Aryl or C1-C6An alkyl group;
R12is C6-C10Aryl or C1-C6An alkyl group;
R13is nitro or C1-C6An alkoxy group.
In certain embodiments, R6And R7Independently hydrogen, by one or more R9Substituted C6-C14Aryl radical, C6-C14Aryl radicals, substituted by one or more R10Substituted C1-C6Alkyl radical, C1-C6Alkyl or-C (═ O) R11(ii) a Or, R6And R7And the above R6And R7Form a 3-8 membered heterocycloalkyl group.
In certain embodiments, when R6And R7Independently by one or more R9Substituted C6-C14When aryl, said is substituted by one or more R9Substituted C6-C14C in aryl6-C14Aryl is C6-C10Aryl, for example phenyl or naphthyl, for example phenyl.
In certain embodiments, when R6And R7Independently is C6-C14When aryl, said C6-C14Aryl is C6-C10Aryl, for example phenyl or naphthyl, for example phenyl.
In certain embodiments, when R6And R7Independently by one or more R10Substituted C1-C6When alkyl, said is substituted by one or more R10Substituted C1-C6C in alkyl1-C6Alkyl is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and also methyl radicals.
In certain embodiments, when R6And R7Independently is C1-C6When alkyl, said C1-C6Alkyl is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and also methyl radicals.
In certain embodiments, when R11Is C6-C10When aryl, said C6-C10Aryl is phenyl or naphthyl, for example phenyl.
In certain embodiments, when R11Is C1-C6When alkyl, said C1-C6Alkyl is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and also methyl radicals.
In certain embodiments, when R6And R7And the above R6And R7When the nitrogen atom in between forms a 3-8 membered heterocycloalkyl group, said 3-8 membered heterocycloalkyl group is a 5-7 membered heterocycloalkyl group, for example a 6 membered heterocycloalkyl group; in the 3-to 8-membered heterocycloalkyl group, the 5-to 7-membered heterocycloalkyl group and the 6-membered heterocycloalkyl group, the remaining hetero atoms are preferably oxygen, and the number of the remaining hetero atoms is preferably 1.
In certain embodiments, R9Is C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and also methyl radicals.
In certain embodiments, R10Is phenyl or naphthyl, for example phenyl.
In certain embodiments, when R8Is C6-C14When aryl, said C6-C14Aryl is C6-C10Aryl, such as phenyl or naphthyl.
In certain embodiments, when R8Is represented by one or more R13Substituted C6-C14When aryl, said is substituted by one or more R13Substituted C6-C14C in aryl6-C14Aryl is C6-C10Aryl, for example phenyl or naphthyl, for example phenyl.
In some implementationsIn the scheme, when R13Is C1-C6At alkoxy, said C1-C6Alkoxy is C1-C4Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, and further for example methoxy.
In certain embodiments, the compound of formula X is
In certain embodiments, the compound of formula XI is
In the Buchwald-Hartwig reaction, the protective gas can be a protective gas conventional in the reaction of the type in the field, and nitrogen or argon, such as nitrogen, is particularly preferred in the present invention.
In the Buchwald-Hartwig reaction, the solvent can be a solvent which is conventional in the reaction in the field, and the invention particularly preferably selects one or more of an alcohol solvent, an ether solvent, an amide solvent, a sulfone solvent and an aromatic hydrocarbon solvent, further preferably selects one or more of an alcohol solvent, an ether solvent and an aromatic hydrocarbon solvent, and further preferably selects an alcohol solvent and/or an ether solvent. The alcoholic solvent is preferably tert-butanol and/or tert-amyl alcohol, for example tert-amyl alcohol. The ether solvent is preferably 1, 4-dioxane. The amide solvent is preferably N-methyl pyrrolidone and/or N, N-dimethyl acetamide. The sulfone solvent is preferably dimethyl sulfoxide. The aromatic hydrocarbon solvent is preferably toluene.
In the Buchwald-Hartwig reaction, the molar concentration of the compound shown in the formula X in the solvent can be the molar concentration conventional in the reactions in the field, and the invention is particularly preferably 0.1mol/L-2mol/L, such as 0.5mol/L-1mol/L, and further such as 0.78mol/L, 0.76mol/L, 0.75mol/L, 0.64mol/L, 0.60mol/L, 0.63mol/L, 0.77mol/L and 0.66 mol/L.
In the Buchwald-Hartwig reaction, the base can be a base conventional in the reaction in the field, and the invention particularly preferably adopts one or more of potassium carbonate, cesium carbonate, potassium phosphate, potassium sulfate, sodium hydroxide, potassium hydroxide and sodium tert-butoxide, such as one or more of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and sodium tert-butoxide, and further such as cesium carbonate and/or sodium hydroxide.
In the Buchwald-Hartwig reaction, the molar ratio of the base to the compound shown in the formula X can be a molar ratio which is conventional in the reaction of the type in the art, and the invention is particularly preferably 1:1 to 2:1, such as 1:1 to 1.7:1, and further such as 1.28:1, 1.32:1, 1.26:1, 1.34:1, 1.24:1, 1.2:1, 1.25:1 and 1.6: 1.
In the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula I and the compound shown in the formula X can be the molar ratio which is conventional in the reaction in the field, and the invention particularly preferably adopts the molar ratio of 0.001:1-0.03:1, such as 0.021:1, 0.017:1, 0.018:1, 0.016:1, 0.0027:1, 0.0034:1 and 0.0017: 1.
In the Buchwald-Hartwig reaction, the molar ratio of the transition metal catalyst to the compound shown in the formula X can be the molar ratio which is conventional in the reaction of the type in the field, and the invention is particularly preferably 0.001:1-0.01:1, such as 0.01:1, 0.0087:1, 0.009:1, 0.0086:1, 0.0083:1, 0.0084:1, 0.0089:1, 0.0088:1, 0.0018:1, 0.0013:1 and 0.0085: 1.
In the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula XI and the compound shown in the formula X can be the molar ratio which is conventional in the reaction of the type in the field, and the invention particularly preferably adopts the molar ratio of 0.1:1-2:1, such as 0.6:1-1:1, further such as 0.81:1, 0.82:1, 0.84:1, 0.85:1, 0.83:1 and 0.79: 1.
In the Buchwald-Hartwig reaction, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction of the type in the field, and the reaction temperature is particularly preferably 80 ℃ to 120 ℃, such as 90 ℃, 100 ℃ and 110 ℃ in the invention.
In the Buchwald-Hartwig reaction, the reaction time of the reaction can be the reaction time conventional in the reaction of the type in the field, and the reaction time is particularly preferably 0.5h to 20h, such as 0.5h to 18h, and further such as 0.5h to 1h, 1h to 1.5h, 1h to 2.5h, 2h to 3h, 3h to 4h, 2h to 2.5h and 6h to 18 h.
In the Buchwald-Hartwig reaction, the reaction may include the following steps: mixing the solvent, the alkali, the compound shown in the formula X and the compound shown in the formula XI, and mixing the mixture with the compound shown in the formula I and the transition metal catalyst for reaction under the protection gas.
In the Buchwald-Hartwig reaction, the reaction can further comprise a post-treatment step after the reaction is finished. The post-treatment steps can be cooling, quenching reaction, extraction, washing, drying, concentration and purification. The cooling may be to room temperature. The reagent used for quenching the reaction may be water. The reagent used for the extraction may be ethyl acetate. The washing reagent may be a saturated saline solution. The reagent used for drying can be anhydrous sodium sulfate. The purification mode can be column chromatography. The eluent used for the column chromatography can be ethyl acetate and petroleum ether.
The preparation method of the compound shown in the formula XII comprises the following steps: under the action of alkali, the compound shown in the formula I and the transition metal catalyst in a solvent under the protection of gas, carrying out the Suzuki reaction shown in the formula XIII and the compound shown in the formula IX to obtain the compound shown in the formula XII,
wherein R is14Is C6-C14Aryl, or, by one or more R16Substituted C6-C14An aryl group;
X4is halogen;
R15independently of one another, halogen, C1-C4Alkyl, nitro or C1-C4An alkoxy group;
m is 1,2, 3, 4 or 5;
R16is nitro or C1-C4An alkoxy group.
In certain embodiments, said R is14Is represented by one or more R16Substituted C6-C14And (4) an aryl group.
In certain embodiments, said R is15Independently a halogen.
In certain embodiments, m is 1.
In certain embodiments, said R is16Is nitro.
In certain embodiments, when said R is14Is represented by one or more R16Substituted C6-C14When aryl, said is substituted by one or more R16Substituted C6-C14C in aryl6-C14Aryl is C6-C10Aryl, for example phenyl or naphthyl, for example phenyl.
In certain embodiments, said X4Is fluorine, chlorine, bromine or iodine, for example chlorine.
In certain embodiments, when said R is15Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine.
In certain embodiments, the compound of formula XIII is
In certain embodiments, the compound of formula IX is
In the Suzuki reaction, the protective gas may be a protective gas conventional in the art, and nitrogen or argon, such as nitrogen, is particularly preferred in the present invention.
In the Suzuki reaction, the solvent can be a solvent which is conventional in the reaction in the field, and the invention particularly preferably adopts an ether solvent, such as tetrahydrofuran.
In the Suzuki reaction, the molar concentration of the compound represented by the formula XIII in the solvent can be the molar concentration conventional in the reactions of the type in the art, and the present invention is particularly preferably 0.1mol/L to 3mol/L, such as 1.5mol/L to 2.5mol/L, and further such as 1.95 mol/L.
In the Suzuki reaction, the base may be a base conventional in the art for such reactions, and in particular, a carbonate salt, such as potassium carbonate, is preferred in the present invention.
In the Suzuki reaction, the molar ratio of the base to the compound of formula XIII may be the molar ratio customary in reactions of this type, and the present invention is particularly preferably from 1:1 to 2:1, for example from 1:1 to 1.5:1, and further for example from 1.23: 1.
In the Suzuki reaction, the molar ratio of the compound shown in the formula I and the compound shown in the formula XIII can be the molar ratio which is conventional in the reactions of the type in the field, and the invention particularly preferably has a molar ratio of 0.0001:1-0.001:1, for example 0.0004: 1.
In the Suzuki reaction, the molar ratio of the transition metal catalyst to the compound of formula XIII may be the molar ratio customary in reactions of this type in the art, and in the present invention is particularly preferably from 0.0001:1 to 0.001:1, for example 0.0004: 1.
In the Suzuki reaction, the molar ratio of the compound of formula IX to the compound of formula XIII can be a molar ratio customary in reactions of this type in the art, and the present invention is particularly preferably from 0.1:1 to 2:1, for example from 0.6:1 to 1:1, for example again from 0.82: 1.
In the Suzuki reaction, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction of the type in the field, and the temperature of 40 ℃ to 80 ℃, such as 60 ℃ is particularly preferred in the invention.
In the Suzuki reaction, the reaction time of the reaction can be the reaction time conventional in the art, and the reaction time is particularly preferably 1h to 10h, such as 3h to 6h, and further such as 4h to 5 h.
In the Suzuki reaction, the reaction may include the steps of: mixing the solvent, the alkali, the compound shown in the formula XIII and the compound shown in the formula IX, and mixing the mixture with the compound shown in the formula I and the transition metal catalyst for reaction under the protection gas.
In the Suzuki reaction, the post-treatment step can be further included after the reaction is finished. The post-treatment steps can be cooling, quenching reaction, extraction, washing, drying, concentration and purification. The cooling may be to room temperature. The reagent used for quenching the reaction may be water. The reagent used for the extraction may be ethyl acetate. The washing reagent may be a saturated saline solution. The reagent used for drying can be anhydrous sodium sulfate. The purification mode can be column chromatography. The eluent used for the column chromatography can be ethyl acetate and petroleum ether.
The invention also provides a compound shown as a formula II,
wherein R is1、R2And R3As defined above.
In certain embodiments, the compound of formula II is
In the present invention, the room temperature means 25 to 30 ℃.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the pyrazole bis-triazole phosphine compound has stable property, excellent catalytic effect and high selectivity, and can be applied to catalytic coupling of amine, boric acid compounds and halides.
Drawings
FIG. 1 is a structural diagram of X-ray diffraction of a single crystal of ligand L1.
FIG. 2 is a structural diagram of X-ray diffraction of a single crystal of ligand L2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The analytical methods of liquid phase detection in examples, application examples and comparative examples are as follows:
1.1 instrumentation
High performance liquid chromatograph: agilent LC 1260(LC chemical workstation) or equivalent HPLC system
A chromatographic column: agilent, SDB-C18250X 4.6mm, 5 μm
1.2 Primary reagents and materials
Acetonitrile (HPLC grade)
Ultrapure water
Phosphoric acid (85%, analytical grade)
1.3 chromatographic conditions:
flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 220nm
Sample introduction amount: 1 μ L
Operating time: 30min
The balance time is as follows: 5min
1.4 Mobile phase
Mobile phase A: 0.1% H3PO4Aqueous solution (1mL H3PO4To 1000mL of ultrapure water)
Mobile phase B: acetonitrile
The gradient elution procedure was:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 15 | 10 | 90 |
| 30 | 10 | 90 |
Example 1
Into a 250mL three-necked flask, 0.089mol (20g) of dibenzoylmethane and 80mL of NMP were added and dissolved with stirring, and the reaction mixture was transparent in pale yellow color (dissolved at elevated temperature or ultrasonically dissolved under ultrasonic waves if necessary). 0.107mol (17.20g) of bromine was slowly added dropwise from a constant pressure dropping funnel at room temperature. The persistent red color is the sign of the reaction termination. After the reaction, 80mL of water was slowly added dropwise to the reaction mixtureA pale yellow solid slowly precipitated. The reaction solution was incubated for 1h in an ice-water bath. The reaction solution was filtered with suction through a sand funnel, and the obtained solid was washed with 3 times of 3X 50mL of water. Then recrystallized from 65mL of absolute ethanol (80 ℃ C. for dissolution under reflux). Then, the mixture was filtered through a sand-core funnel, and the filter cake was washed with 3 times of 3X 30mL of absolute ethanol. 26.20g of product alpha-bromodibenzoylmethane is obtained. The purity by liquid phase detection is 98.5%, and the yield is 95.44%. Alpha-bromodibenzoylmethane1H NMR(400MHz,DMSO)：δ＝8.02(d,J＝7.3Hz,4H),7.81(s,1H),7.69(t,J＝7.4Hz,2H),7.56(t,J＝7.7Hz,4H)。
To a 100mL three-necked flask, 0.132mol (12.66g, 95%) of 1,2, 4-triazole sodium salt and 40mL of an ultrapure solvent DMF were added, and the reaction solution was turbid. The oxygen in the reaction flask was evacuated and replaced with nitrogen three times. Then, 0.066mol (20g) of α -bromodibenzoylmethane was dissolved in 30mL of an ultrapure solvent DMF, and the resulting solution was placed in a dropping funnel. Slowly dropwise adding at room temperature, and after dropwise adding the alpha-bromodibenzoylmethane, raising the temperature to 45 ℃. When the color of the reaction solution became reddish brown, the reaction was continued for about 2 hours, and then 60mL of acetic acid was added and stirred for 25 min. Then, 0.099mol (5.92g, 85%) of hydrazine hydrate was dissolved in 10mL of DMF, and the solution was added to a dropping funnel, and slowly dropped at 45 ℃ to observe that the color of the reaction solution became light after the dropping, and after about 15min, a large amount of solid was observed to be precipitated from the reaction solution, and the reaction was continued for 1h to stop the reaction. The reaction solution was slowly cooled, and then 90mL of water was slowly dropped. The temperature of the reaction solution was lowered to 0 ℃ and kept for 1 h. The resulting reaction solution was then filtered with a sand funnel, and the filter cake was washed with 3X 60mL of water and then 3X 50mL of n-heptane. The solid was drained by oil pump at 35 ℃. 18.57g of white solid 1- (3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole is obtained, the purity is 94.5% by liquid phase detection, and the yield is 92.56%. 1- (3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole1H NMR(400MHz,DMSO)：δ＝13.97(s,1H),8.77(s,1H),8.37(s,1H),7.34(dd,J＝36.9,16.3Hz,10H)。
Into a 100mL three-necked flask, 0.035mol (10.09g) of 1- (3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole, 0.088mol (12.14g) of potassium carbonate, and 52mL of NMP were added. Stir at room temperature for 25 minutes. Then, 0.044mol (6.82g) of ethyl iodide was dissolved in 6.5mL of NMP, and the solution was added to the dropping funnel and slowly dropped at room temperature. The reaction solution became brown-yellow in color. The reaction was continued for 3h, the color of the reaction solution became tan, indicating the end of the reaction. After the reaction mixture was cooled, 70mL of water was added to the reaction mixture. The resulting reaction solution was filtered with a sand funnel, and the filter cake was washed with 3X 50mL of water. Then recrystallized from 80mL of toluene (90 ℃ C. for dissolution under reflux). And then, carrying out suction filtration by using a sand core funnel to obtain a white solid. And (3) drying the solid by using an oil pump at 35 ℃ to obtain 10.84g of 1- (1-ethyl-3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole. The purity by liquid phase detection is 98.7%, and the yield is 96.56%. 1- (1-ethyl-3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole1H NMR(400MHz,DMSO)：δ＝8.69(s,1H),8.16(s,1H),7.50–7.22(m,10H),4.15(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H)。
Into a 100mL four-necked flask, 6.342mmol (2g) of 1- (1-ethyl-3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole and 24mL of ultra-dry solvent THF were added, and the mixture was slightly heated to aid dissolution. Mixing liquid nitrogen and ethanol, making an ultralow temperature device, cooling the reaction liquid to-80 ℃, then replacing air in the reaction system with nitrogen, and reacting under the protection of nitrogen. 9.525mmol (3.81mL,2.5mol/L) of n-butyllithium were slowly added dropwise while the temperature of the reaction mixture was maintained at-80 ℃ while maintaining the temperature between-75 ℃ and-80 ℃. After completion of the dropwise addition, the reaction solution was slowly warmed to 0 ℃ and maintained at this temperature for 1 hour. Then cooling to-80 ℃, then replacing the air of the reaction system with nitrogen, and reacting under the protection of nitrogen. The temperature of the reaction solution was maintained at9.937mmol (1.87g, 96%) of di-tert-butylphosphine chloride are slowly added dropwise at-80 ℃ while maintaining the temperature between-75 ℃ and-80 ℃. After the dropwise addition is finished, the temperature is slowly raised to the room temperature, and the mixture is stirred for 10 to 15 hours at the room temperature. After completion of the reaction, the reaction mixture was quenched with 30mL of water, extracted with EA (3X 50 mL), dried over 10g of anhydrous sodium sulfate, and then desolventized (55 ℃ C., 50mbar) to give an oily liquid. Then purifying by column chromatography under the protection of nitrogen, wherein the used solvents are petroleum ether (60-90 ℃) and ethyl acetate, the column height is 19cm, the diameter is 3cm, and the ratio of the petroleum ether to the ethyl acetate is 15:1, so as to obtain a final product, namely 2.87g of white solid 5-di-tert-butyl-1- (1-ethyl-3, 5-diphenyl-1H-pyrazole-4-bi) -1H-1,2, 4-triazole. The purity by liquid phase detection is 97.7%, and the yield is 96.36%. 5-di-tert-butyl-1- (1-ethyl-3, 5-diphenyl-1H-pyrazole-4-bi) -1H-1,2, 4-triazole1H NMR(400MHz,CD3OD)：δ＝8.36(s,1H),7.55–7.20(m,10H),4.36(dd,J＝14.0,7.1Hz,1H),4.28(dd,J＝14.0,7.1Hz,1H),1.43(t,J＝7.2Hz,3H),0.69(dd,J＝14.6,12.6Hz,18H).
Example 2
Into a 100mL four-necked flask, 6.342mmol (2g) of 1- (1-ethyl-3, 5-phenyl-1-H-pyrazole-4-bis) -1H-1,2, 4-triazole (prepared in example 1) and 24mL of THF (ultra-dry solvent) were added and slightly heated to aid dissolution. Mixing liquid nitrogen and ethanol, making an ultralow temperature device, cooling the reaction liquid to-80 ℃, then replacing air in the reaction system with nitrogen, and reacting under the protection of nitrogen. 9.525mmol (3.81mL,2.5mol/L) of n-butyllithium were slowly added dropwise while the temperature of the reaction mixture was maintained at-80 ℃ while maintaining the temperature between-75 ℃ and-80 ℃. After completion of the dropwise addition, the reaction solution was slowly warmed to 0 ℃ and maintained at this temperature for 1 hour. Then cooling to-80 ℃, then replacing the air of the reaction system with nitrogen, and reacting under the protection of nitrogen. 9.870mmol (2.47g, 93%) dicyclohexyl phosphonium chloride was slowly added dropwise while the temperature of the reaction solution was maintained at-80 ℃ and maintained at-75 ℃ to-80 ℃. The dripping is finishedAfter the reaction is finished, slowly raising the temperature to room temperature, and stirring at room temperature for 10-15 h. After completion of the reaction, the reaction mixture was quenched with 30mL of water, extracted with EA (3X 50 mL), dried over 10g of anhydrous sodium sulfate, and then desolventized (55 ℃ C., 50mbar) to give an oily liquid. Then purifying by column chromatography under the protection of nitrogen, wherein the used solvents are petroleum ether (60-90 ℃) and ethyl acetate, the column height is 19cm, the diameter is 3cm, and the ratio of the petroleum ether to the ethyl acetate is 20:1, so as to obtain the final product, and 3.22g of white crystal 5-dicyclohexyl-1- (1-ethyl-3, 5-diphenyl-1H-pyrazole-4-bi) -1H-1,2, 4-triazole is obtained. The purity by liquid phase detection was 96.7%, and the yield was 96.10%. 5-dicyclohexyl-1- (1-ethyl-3, 5-diphenyl-1H-pyrazole-4-bi) -1H-1,2, 4-triazole1H NMR(400MHz,CDCl3)：δ＝8.25(s,1H),7.34(ddd,J＝39.1,16.9,5.5Hz,10H),4.29(dt,J＝10.5,6.8Hz,2H),1.79–0.21(m,25H)。
EXAMPLE 3 Single Crystal of ligand L1
Adding about 100 mg-150 mg of ligand L1 into a sample bottle, slowly adding anhydrous methanol to completely dissolve the solid in the sample, pricking a small hole on the bottle cap of the sample bottle, placing into an evaporator filled with nitrogen, standing for 1 month, and growing crystal. Subjecting the crystal to X-ray diffraction detection, such as the structure shown in FIG. 1, in accordance with the target structure.
EXAMPLE 4 Single Crystal of ligand L2
Adding about 100 mg-150 mg of ligand L2 into a sample bottle, slowly adding anhydrous acetone to completely dissolve the solid in the sample, pricking a small hole on the bottle cap of the sample bottle, placing into an evaporator filled with nitrogen, standing for 1 month, and growing crystal. Subjecting the crystal to X-ray diffraction detection, such as the structure shown in FIG. 2, in accordance with the target structure.
Application example 1 catalytic Synthesis of N-phenylmorpholine
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added216mg (0.034mmol, 97%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-phenylmorpholine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 98.7%, the conversion rate of the raw material is 100%, and the yield is 96.95%.
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 0.78g (2.394mmol) cesium carbonate, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added218mg (0.035mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 1-2 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then using ethyl acetate and petroleum ether to obtain the product by column chromatographyThe product is N-phenyl morpholine. The purity of the liquid phase detection is 98.5%, the conversion rate of the raw material is 100%, and the yield is 97.95%.
Product N-phenylmorpholine:1H NMR(400MHz,DMSO)：δ＝7.21(t,J＝7.6Hz,2H),6.91(d,J＝7.9Hz,2H),6.78(t,J＝7.0Hz,1H),3.71(s,4H),3.06(s,4H).
application example 2 catalytic Synthesis of N- (2, 6-dimethylphenyl) aniline
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.23g (1.898mmol)2, 6-dimethylaniline, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added216mg (0.034mmol, 97%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N- (2, 6-dimethylphenyl) aniline is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 99.3 percent, the conversion rate of the raw material is 100 percent, and the yield is 94.95 percent.
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.23g (1.898mmol)2, 6-dimethylaniline, 0.78g (2.394mmol) cesium carbonate, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added218mg (0.035mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 2-3 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then using ethyl acetate and petroleum etherThe product N- (2, 6-dimethylphenyl) aniline is obtained by column chromatography. The purity of the liquid phase detection is 98.9%, the conversion rate of the raw material is 100%, and the yield is 93.95%.
Product N- (2, 6-dimethylphenyl) aniline:1H NMR(400MHz,DMSO):δ＝7.26(s,1H),7.18–6.92(m,5H),6.55(t,J＝7.1Hz,1H),6.38(d,J＝7.7Hz,2H),2.11(s,6H).
application example 3 catalytic Synthesis of N-methyldiphenylamine
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.20g (1.866mmol) N-methylaniline, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 9mg (0.016mmol) Pd (dba) is added215mg (0.032mmol, 97%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-methyldiphenylamine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 99.3%, the conversion rate of the raw material is 100%, and the yield is 94.40%.
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.20g (1.866mmol) N-methylaniline, 0.78g (2.394mmol) cesium carbonate, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 9mg (0.016mmol) Pd (dba) is added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then using acetic acid BThe ester and petroleum ether are subjected to column chromatography to obtain the product N-methyldiphenylamine. The purity of the liquid phase detection is 98.5%, the conversion rate of the raw material is 100%, and the yield is 95.10%.
The product N-methyldiphenylamine:1H NMR(400MHz,DMSO):δ＝7.23(t,J＝7.7Hz,4H),7.06–6.86(m,6H),3.21(s,3H)。
application example 4 catalytic Synthesis of N-methyl-N-benzylaniline
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.23g (1.898mmol) N-methylbenzylamine, 0.78g (2.394mmol) cesium carbonate, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 9mg (0.016mmol) Pd (dba) is added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 3-4 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-methyl-N-benzyl aniline is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 97.8%, the conversion rate of raw materials is 100%, and the yield is 93.24%.
Product N-methyl-N-benzylaniline:1H NMR(400MHz,DMSO):δ＝7.40–7.04(m,7H),6.77–6.56(m,3H),4.52(s,2H),2.96(s,3H)。
application example 5 catalytic Synthesis of 4- (1-naphthyl) morpholine
To a 25mL branched reaction tube were added 0.25g (1.207mmol) of 1-bromonaphthalene, 0.13g (1.492mmol) of morpholine, 0.78g (2.394mmol) of cesium carbonate, and 2.5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under the protection of nitrogenNext, 9mg (0.016mmol) of Pd (dba) was added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 2-3 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 4- (1-naphthyl) morpholine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 97.8%, the conversion rate of the raw material is 100%, and the yield is 95.24%.
Product 4- (1-naphthyl) morpholine:1H NMR(400MHz,DMSO):δ＝8.14(d,J＝7.2Hz,1H),7.87(d,J＝6.6Hz,1H),7.48(ddd,J＝34.9,28.1,8.0Hz,4H),7.10(d,J＝7.3Hz,1H),3.84(s,4H),2.98(s,4H)。
application example 6 catalytic Synthesis of 4- (3-methoxyphenyl) morpholine
To a 25mL branched reaction tube were added 0.25g (1.337mmol) of m-bromoanisole, 0.14g (1.607mmol) of morpholine, 0.08g (2.000mmol) of sodium hydroxide, and 2.5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, add 8.3mg (0.014mmol) Pd (dba)212.9mg (0.027mmol, 96%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 4- (3-methoxyphenyl) morpholine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 98.5%, the conversion rate of the raw material is 100%, and the yield is 97.77%.
Product 4- (3-methoxyphenyl) morpholine:1H NMR(400MHz,DMSO):δ＝7.10(t,J＝8.1Hz,1H),6.60–6.31(m,3H),3.70(s,7H),3.06(s,4H).
application example 7 catalytic Synthesis of 4- (4-nitrophenyl) morpholine
To a 25mL branched reaction tube were added 0.25g (1.238mmol) of p-bromonitrobenzene, 0.13g (1.492mmol) of morpholine, 0.08g (2.000mmol) of sodium hydroxide, and 2.5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 7.5mg (0.013mmol) Pd (dba) were added212.0mg (0.025mmol, 96%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 4- (4-nitrophenyl) morpholine is obtained by column chromatography using ethyl acetate and petroleum ether. The purity by liquid phase detection is 97.9%, the conversion rate of the raw material is 100%, and the yield is 96.64%.
Product 4- (4-nitrophenyl) morpholine:1H NMR(400MHz,DMSO)：δ＝8.05(d,J＝9.2Hz,2H),7.02(d,J＝9.2Hz,2H),3.71(s,4H),3.39(s,4H)。
application example 8 catalytic Synthesis of N- (2-methoxyphenyl) -2, 6-xylidine
To a 25mL branched reaction tube were added 0.25g (1.337mmol) o-bromoanisole, 0.19g (1.568mmol)2, 6-dimethylaniline, 0.08g (2.000mmol) sodium hydroxide and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 7.7mg (0.013mmol) Pd (dba) were added212.8mg (0.027mmol, 96%) L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After the reaction was completed, it was cooled to room temperature, 15mL of water was added thereto, and the mixture was usedThe extract was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N- (2-methoxyphenyl) -2, 6-xylidine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 98.5%, the conversion rate of the raw material is 100%, and the yield is 97.6%.
To a 25mL branched reaction tube were added 0.25g (1.337mmol) o-bromoanisole, 0.20g (1.650mmol)2, 6-dimethylaniline, 0.08g (2.000mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, add 8.2mg (0.014mmol) Pd (dba)215mg (0.028mmol, 95%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out for 1 hour under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N- (2-methoxyphenyl) -2, 6-xylidine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 98.3%, the conversion rate of the raw material is 100%, and the yield is 94.6%.
Product N- (2-methoxyphenyl) -2, 6-xylidine:1H NMR(400MHz,DMSO)：δ＝7.09(t,J＝9.0Hz,3H),6.88(d,J＝7.3Hz,1H),6.69–6.51(m,2H),6.46(s,1H),5.84(d,J＝6.9Hz,1H),3.85(s,3H),2.08(s,6H)。
application example 9 catalytic Synthesis of 2, 6-dimethyl-N- (2-nitrophenyl) aniline
To a 25mL branched reaction tube were added 0.25g (1.238mmol) of o-bromonitrobenzene, 0.19g (1.568mmol) of 2, 6-dimethylaniline, 0.61g (1.872mmol) of cesium carbonate and 2.5mL ofTert-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 7.8mg (0.014mmol) Pd (dba) are added213.3mg (0.025mmol, 95%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 2, 6-dimethyl-N- (2-nitrophenyl) aniline is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 98.6%, the conversion rate of the raw material is 100%, and the yield is 95.12%.
application example 10 catalytic Synthesis of 4-methoxy-N-methyl-N-phenylaniline
To a 25mL branched reaction tube were added 0.25g (1.337mmol) of p-bromoanisole, 0.17g (1.586mmol) of N-methylaniline, 0.08g (2.000mmol) of sodium hydroxide and 2.5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, add 8.0mg (0.014mmol) Pd (dba)212.7mg (0.027mmol, 96%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 4-methoxy-N-methyl-N-phenyl aniline is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 99.0 percent, the conversion rate of the raw material is 100 percent, and the yield is 95.63 percent.
The product 4-methoxy-N-methylphenyl-N-phenylaniline:1HNMR(400MHz,DMSO):δ＝7.13(t,J＝7.5Hz,2H),7.05(d,J＝8.5Hz,2H),6.91(d,J＝8.5Hz,2H),6.72(d,J＝7.7Hz,3H),3.72(s,3H),3.16(s,3H)。
application example 11 catalytic Synthesis of 2-Nitro-N-methyl-N-phenylaniline
To a 25mL branched reaction tube were added 0.25g (1.238mmol) o-bromonitrobenzene, 0.16g (1.493mmol) N-methylaniline, 0.61g (1.872mmol) cesium carbonate and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 7.3mg (0.013mmol) of Pd (dba) were added213.1mg (0.024mmol, 95%) L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 1-2.5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product 2-nitro-N-methyl-N-phenylaniline is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 98.3%, the conversion rate of the raw material is 100%, and the yield is 94.33%.
Product 2-nitro-N-methyl-N-phenylaniline:1H NMR(400MHz,DMSO):δ＝7.90(d,J＝7.7Hz,1H),7.72(d,J＝7.3Hz,1H),7.50(d,J＝7.6Hz,1H),7.41(s,1H),7.13(d,J＝6.9Hz,2H),6.76(t,J＝6.2Hz,1H),6.62(d,J＝7.3Hz,2H),3.23(s,3H)。
application example 12 catalytic Synthesis of N-methyldiphenylamine
To a 35mL branched reaction tube were added 0.50g (3.184mmol) of bromobenzene, 0.41g (3.826mmol) of N-methylaniline, 0.19g (4.750mmol) of sodium hydroxide, and 5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. In nitrogenUnder protection of gas, 3.9mg (0.007mmol) of Pd (dba) were added26.3mg (0.013mmol, 96%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 0.5-1 hour under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-methyldiphenylamine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 95.3%, the conversion rate of the raw material is 100%, and the yield is 95.40%.
To a 35mL branched reaction tube were added 1.00g (6.367mmol) of bromobenzene, 0.82g (7.652mmol) of N-methylaniline, 3.11g (9.545mmol) of cesium carbonate, and 10mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 6mg (0.010mmol) of Pd (dba) are added211mg (0.021mmol, 96%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 1-1.5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-methyldiphenylamine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 94.5%, the conversion rate of the raw material is 100%, and the yield is 94.10%.
Application example 13 catalytic Synthesis of N-phenylbenzamide
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.23g (1.899mmol) benzamide, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added216mg (0.034mmol, 97%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃ and under the protection of nitrogenThe reaction is carried out for 6 to 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-phenyl benzamide is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 99.3%, the conversion rate of the raw material is 100%, and the yield is 93.95%.
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.23g (1.899mmol) benzamide, 0.78g (2.394mmol) cesium carbonate, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 9mg (0.016mmol) Pd (dba) is added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 3-4 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-phenyl benzamide is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 97.8%, the conversion rate of raw materials is 91.8%, and the yield is 85.24%.
Product N-phenylbenzamide:1H NMR(400MHz,CDCl3)δ＝7.95(s,1H),7.85(d,J＝7.3Hz,2H),7.64(d,J＝7.7Hz,2H),7.52(d,J＝7.1Hz,1H),7.45(t,J＝7.3Hz,2H),7.35(t,J＝7.6Hz,2H),7.14(t,J＝7.2Hz,1H)。
application example 14 catalytic Synthesis of acetanilide
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.11g (1.862mmol) acetamide, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added216mg (0.034mmol, 97%) of L1 ligand. Then nitrogen is used to empty the reaction systemReplace qi for 3 times. Slowly heating to 100 ℃, and reacting for 6-18 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-acetanilide is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 99.3 percent, the conversion rate of the raw material is 85.8 percent, and the yield is 82.95 percent.
Product N-acetanilide:1H NMR(400MHz,CDCl3)δ＝7.65(s,1H),7.50(d,J＝7.4Hz,2H),7.29(d,J＝7.5Hz,2H),7.10(d,J＝6.5Hz,1H),2.15(s,3H)。
application example 15 catalytic synthesis of 4 '-chloro-2-nitro-1, 1' -biphenyl
5g of 4-chlorobenzeneboronic acid (0.032mol), 6.05g of o-nitrochlorobenzene (0.039mol) and 6.63g of K are added to a 50mL autoclave at room temperature2CO3(0.048mol) and 20mL of tetrahydrofuran. The air in the reaction system was replaced 3 times with nitrogen. Under a nitrogen blanket, 2.84mg (0.016mmol) of palladium chloride and 7.66mg (0.016mmol, 96%) of L1 ligand were added. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 60 ℃, and reacting for 4-5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 25mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 25mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then, the product 4 '-chlorine-2-nitro-1, 1' -biphenyl is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 95.5%, the conversion rate of the raw material is 100%, and the yield is 92.10%.
5g of 4-chlorobenzeneboronic acid (0.032mol), 6.05g of o-nitrochlorobenzene (0.039mol) and 6.63g of K are added to a 50mL autoclave at room temperature2CO3(0.048mol) and 20mL of tetrahydrofuran. The air in the reaction system was replaced 3 times with nitrogen. Under the protection of nitrogen, 2.84mg (0.016mmol) of palladium chloride is added8.53mg (0.016mmol, 96%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 60 ℃, and reacting for 4-5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 25mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 25mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then, the product 4 '-chlorine-2-nitro-1, 1' -biphenyl is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 96.5%, the conversion rate of the raw material is 100%, and the yield is 95.10%.
Product 4 "-chloro-2-nitro-1, 1" -biphenyl: (1H NMR(400MHz,CDCl3):δ＝7.85(dd,J＝8.1,1.2Hz,Ar-H,1H),7.60(td,J＝7.6,1.3Hz,Ar-H,1H),7.48(td,J＝7.8,1.4Hz,Ar-H,1H),7.40-7.34(m,Ar-H,3H),7.25-7.21(m,Ar-H,2H).13C NMR(101MHz,CDCl3):δ＝148.9,135.8,135.0,134.3,132.4,131.7,129.2,128.8,128.5,124.1。
Application example 16
To a branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 2.388mmol base, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added216mg (0.034mmol, 97%) of L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out under nitrogen protection, samples were taken at 1 hour, 2.5 hours and 18 hours, and the conversion of the raw material was measured in liquid phase, and the results are shown in Table 1.
TABLE 1 conversion of bromobenzene under different bases at 1 hour, 2.5 hours, 18 hours
| Serial number | Alkali | 1h | 2.5h | 18h |
| 1 | K2CO3 | 9.2％ | 21.0％ | 100％ |
| 2 | Cs2CO3 | 47.7％ | 100％ | 100％ |
| 3 | K3PO4 | 20.5％ | 33.9％ | 59.6％ |
| 4 | NaOH | 100％ | 100％ | 100％ |
| 5 | KOH | 100％ | 100％ | 100％ |
| 6 | NaOtBu | 100％ | 100％ | 100％ |
| 7 | NaOH (33% water) | 100％ | 100％ | 100％ |
| 8 | KOH (33% water) | 100％ | 100％ | 100％ |
Application example 17
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 2.388mmol base, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 deg.C, and keeping under nitrogenThe reaction was carried out under the protection, samples were taken at 1 hour, 2.5 hours and 18 hours, and the conversion of the raw material was measured in the liquid phase, and the results are shown in Table 2.
TABLE 2 conversion of bromobenzene under different bases at 1 hour, 2.5 hours, 18 hours
| Serial number | Alkali | 1h | 2.5h | 18h |
| 1 | K2CO3 | 9.2％ | 21.0％ | 100％ |
| 2 | Cs2CO3 | 47.7％ | 100％ | 100％ |
| 3 | K3PO4 | 20.5％ | 33.9％ | 59.6％ |
| 4 | NaOH | 100％ | 100％ | 100％ |
| 5 | KOH | 100％ | 100％ | 100％ |
| 6 | NaOtBu | 100％ | 100％ | 100％ |
| 7 | NaOH (33% water) | 100％ | 100％ | 100％ |
| 8 | KOH (33% water) | 100％ | 100％ | 100％ |
Application example 18
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 2.500mmol base, and 2.5mL solvent. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added217mg (0.032mmol, 97%) of L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly raising the temperature to a certain temperature, reacting under the protection of nitrogen, sampling at 1 hour, 2.5 hours and 18 hours respectively, and detecting the conversion rate of the raw materials by a liquid phase, wherein the results are shown in a table 3.
TABLE 3 conversion of bromobenzene at 1 hour, 2.5 hours, 18 hours under different base, temperature and solvent
Application example 19
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.17g (1.951mmol) morpholine, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under the protection of nitrogen, 0.017mmol of catalyst and 0.034mmol of ligand are added. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out under nitrogen protection, samples were taken at 1 hour, 2.5 hours and 18 hours, and the conversion of the raw material was measured in liquid phase, and the results are shown in Table 4.
TABLE 4 conversion of bromobenzene over different catalysts at 1 hour, 2.5 hours, 18 hours
Application example 20
To a 35mL branched reaction tube were added 1.00g (6.367mmol, 1 eq.) of bromobenzene, 0.82g (7.652mmol) of N-methylaniline, 0.38g (9.501mmol) of sodium hydroxide, and 5mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Adding Pd (dba) under the protection of nitrogen2L1 ligand. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out under nitrogen protection, samples were taken at 1 hour, 2.5 hours and 18 hours, and the conversion of the raw material was measured in liquid phase, and the results are shown in Table 5.
To a 35mL branched reaction tube were added 1.00g (6.367mmol, 1 eq.) of bromobenzene, 0.82g (7.652mmol) of N-methylaniline, 3.11g (9.545mmol) of cesium carbonate, and 10mL of t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Adding Pd (dba) under the protection of nitrogen2L2 ligand. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out under nitrogen protection, samples were taken at 1 hour, 2.5 hours and 18 hours, and the conversion of the raw material was measured in liquid phase, and the results are shown in Table 5.
TABLE 5 conversion of bromobenzene at different catalyst to ligand ratios at 1 hour, 2.5 hours, 18 hours
Comparative example 1
To a 25mL branched reaction tube, 0.25g (1) was added337mmol) o-bromoanisole, 0.20g (1.650mmol)2, 6-dimethylaniline, 0.08g (2.000mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, add 8.1mg (0.014mmol) Pd (dba)214.5mg (0.027mmol, 95%) of Bippyphos. The air in the reaction system was replaced with nitrogen 3 times. The temperature was slowly raised to 100 ℃ and the reaction was carried out for 6 hours under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N- (2-methoxyphenyl) -2, 6-xylidine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 94.3%, and the conversion rate is 78.1%. The yield thereof was found to be 65.4%.
The conditions of this comparative example are identical to those of example 8, with the difference that the ligands differ. Compared with ligands L1 and L2, the application of Bippyphos in Buchwald-Hartwig reaction has longer reaction time, lower conversion rate of raw materials and lower yield of products.
Comparative example 2
To a 25mL branched reaction tube were added 0.25g (1.592mmol) bromobenzene, 0.20g (1.867mmol) N-methylaniline, 0.10g (2.500mmol) sodium hydroxide, and 2.5mL t-amyl alcohol. The air in the reaction system was replaced 3 times with nitrogen. Under nitrogen protection, 10mg (0.017mmol) Pd (dba) are added20.017mg (0.032mmol, 95%) of Bippyphos ligand. The air in the reaction system was replaced with nitrogen 3 times. Slowly heating to 100 ℃, and reacting for 6-18 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 15mL of water was added, and the mixture was extracted 3 times with ethyl acetate (3X 15mL) and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then the product N-methyldiphenylamine is obtained by column chromatography with ethyl acetate and petroleum ether. The purity by liquid phase detection is 95.3%, the conversion rate of the raw material is 100%, and the yield is 94.40%.
This comparative example and application example 12 comparison shows that when the bipyphos ligand is applied to the Buchwald-Hartwig reaction, similar conversion of the starting material and yield of the product are achieved, with a larger amount of ligand required and a longer reaction time than when the ligands L1 and L2 are applied.
Comparative example 3
To a 100mL three-necked flask, 0.016mol (5g) of alpha-bromodibenzoylmethane, 2 equivalents of a reagent and 18mL of a solvent were added, the temperature was slowly raised to 45 ℃ and the reaction was carried out at 45 ℃ for 6 to 12 hours, and the liquid phase detection reaction showed the results in Table 6.
TABLE 6 content of product under different conditions
| Serial number | Reagent | Solvent(s) | Content of product% | Content of by-products% |
| 1 | 1,2,4 triazole | Non-ultra-dry DMF | 17.8％ | 75.9％ |
| 2 | 1,2,4 triazole | Ultra-dry DMF | 51.9％ | 37.5％ |
| 3 | 1,2,4 triazole sodium | Non-ultra-dry DMF | 73.6％ | 16.8％ |
| 4 | 1,2,4 triazole sodium | Ultra-dry DMF | 95.6％ | 0.8％ |
Comparative example 4
To a 100mL three-necked flask, 0.032mol (3.07g, 95%) of 1,2, 4-triazole sodium salt and 10mL of an ultrapure solvent DMF were added, and the reaction solution was turbid. The oxygen in the reaction flask was evacuated and replaced with nitrogen three times. Then, 0.016mol (5g) of alpha-bromodibenzoylmethane was dissolved in 7.5mL of an ultrapure solvent DMF, and the resulting solution was placed in a dropping funnel. Slowly dropwise adding at room temperature, and after dropwise adding the alpha-bromodibenzoylmethane, raising the temperature to 45 ℃. After the reaction solution became reddish brown, the reaction was continued for about 2 hours, and then 15mL of acetic acid was added and stirred for 25 min. Then, 0.024mol (2.60g) of phenylhydrazine was dissolved in 4mL of DMF, and the solution was added to the dropping funnel, slowly dropped at 45 ℃ and, after completion of the dropping, the reaction was continued for 3 to 6 hours. After completion of the reaction, it was found that a large amount of by-products were produced, and it was not possible to determine whether the product was formed.
Comparative example 5
Into a 100mL three-necked flask, 0.017mol (5g) of 1- (3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole and 20mL of NMP were added. Slowly heating to 80 deg.C to dissolve the raw materials completely. Then, 0.026mol (3.29g) of dimethyl sulfate was dissolved in 6.5mL of NMP, and the solution was added to the dropping funnel and slowly dropped at 80 ℃. As the reaction proceeded, the reaction liquid became brown-yellow in color. The reaction is continued for 6 to 10 hours, and the color of the reaction solution is changed into tan. After the reaction mixture was cooled, 20mL of water and 20mL of ethyl acetate were added to the reaction mixture. After the liquid separation, the mother liquor was extracted with 3X 20mL of ethyl acetate and washed once with 30mL of saturated brine. Then dried over 5g of anhydrous sodium sulfate and desolventized (55 ℃ C., 50 mbar). Then, 2.47g of 1- (1-methyl-3, 5-phenyl-1-H-pyrazole-4-bi) -1H-1,2, 4-triazole is obtained by column chromatography with ethyl acetate and petroleum ether. The purity of the liquid phase detection is 96.3 percent, and the conversion rate is 54.1 percent. The yield thereof was found to be 45.42%.
Claims (27)
1. A compound shown as a formula I is provided,
wherein R is1Is hydrogen, C1-C6Alkyl or phenyl;
R2and R3Is phenyl;
R4and R5Independently is C1-C6Alkyl radical, C3-C8Cycloalkyl or phenyl.
2. A compound of formula I according to claim 1,
when said R is1Is C1-C6When alkyl, said C1-C6Alkyl is C1-C4An alkyl group;
and/or, when said R is4And R5Independently is C1-C6When alkyl, said C1-C6Alkyl is C1-C4An alkyl group;
and/or, when said R is4And R5Independently is C3-C8When there is a cycloalkyl group, said C3-C8Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
3. A compound of formula I according to claim 2,
when said R is1Is C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or, when said R is4And R5Independently is C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or, when said R is4And R5Independently is C3-C8When there is a cycloalkyl group, said C3-C8Cycloalkyl is cyclohexyl.
4. A compound of formula I according to claim 3,
when said R is1Is C1-C6When alkyl, said C1-C6Alkyl is ethyl;
and/or, when said R is4And R5Independently is C1-C6When alkyl, said C1-C6The alkyl group is a tert-butyl group.
5. A compound of formula I according to any one of claims 1 to 4,
said R1Is C1-C6An alkyl group;
and/or, said R4And R5Independently is C1-C6Alkyl or C3-C8A cycloalkyl group;
and/or, said R4And R5The same is true.
6. The compound of formula I according to claim 1, wherein the compound of formula I is
7. A catalyst composition, comprising a compound of formula I according to any one of claims 1 to 6 and a transition metal catalyst.
8. The catalyst composition of claim 7,
the catalyst consists of a compound as shown in the formula I in any one of claims 1 to 6 and a transition metal catalyst;
and/or, the transition metal catalyst is Pd (dba)2One or more of palladium chloride and palladium acetate;
and/or the molar ratio of the compound shown as the formula I to the transition metal catalyst is 1:1-10: 1;
and/or all or part of the compound shown in the formula I and all or part of the transition metal catalyst exist in a complex form.
9. The catalyst composition of claim 8,
the transition metal catalyst is Pd (dba)2And/or palladium chloride;
and/or the molar ratio of the compound shown as the formula I to the transition metal catalyst is 1:1-2.5: 1.
10. The catalyst composition of claim 8,
the molar ratio of the compound shown as the formula I to the transition metal catalyst is 1.79:1, 1.86:1, 1.93:1, 2.07:1 or 2.1: 1.
11. Use of a compound of formula I according to any one of claims 1 to 6 or a catalyst composition according to any one of claims 7 to 10 in a coupling reaction.
12. Use according to claim 11, characterized in that it is any of the following solutions:
the first scheme is as follows: which comprises the following steps: under the action of alkali, the compound shown in the formula I and the transition metal catalyst in a solvent under the protection gas, carrying out Buchwald-Hartwig reaction shown in the specification on the compound shown in the formula X and the compound shown in the formula XI to obtain the compound shown in the formula IX,
wherein R is6And R7Independently hydrogen, by one or more R9Substituted C6-C14Aryl radical, C6-C14Aryl radicals, substituted by one or more R10Substituted C1-C6Alkyl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl or-C (═ O) R11(ii) a Or R6And R7And the above R6And R7Form a 3-to 8-membered heterocycloalkyl group with the nitrogen atom in between, or, by one or more R12Substituted 3-8 membered heterocycloalkyl; wherein, 3-8 membered heterocycloalkyl is substituted with one or more R11Substituted 3-8 membered heterocycloalkylIn the 3-to 8-membered heterocycloalkyl group of (A), in addition to the above-mentioned R6And R7The rest heteroatoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of the rest heteroatoms is 0, 1,2 or 3;
R8is C6-C14Aryl, or, by one or more R13Substituted C6-C14An aryl group;
X3is halogen;
R9is C1-C6An alkyl group;
R10is C6-C10An aryl group;
R11is C6-C10Aryl or C1-C6An alkyl group;
R12is C6-C10Aryl or C1-C6An alkyl group;
R13is nitro or C1-C6An alkoxy group;
scheme II: which comprises the following steps: under the action of alkali, the compound shown in the formula I and the transition metal catalyst in a solvent under the protection of gas, carrying out the Suzuki reaction shown in the formula XIII and the compound shown in the formula IX to obtain the compound shown in the formula XII,
wherein R is14Is C6-C14Aryl, or, by one or more R16Substituted C6-C14An aryl group;
X4is halogen;
R15independently of one another, halogen, C1-C4Alkyl, nitro or C1-C4An alkoxy group;
m is 1,2, 3, 4 or 5;
R16is nitro or C1-C4An alkoxy group.
13. The use according to claim 12,
when R is6And R7Independently by one or more R9Substituted C6-C14When aryl, said is substituted by one or more R9Substituted C6-C14C in aryl6-C14Aryl is C6-C10An aryl group;
and/or when R6And R7Independently is C6-C14When aryl, said C6-C14Aryl is C6-C10An aryl group;
and/or when R6And R7Independently by one or more R10Substituted C1-C6When alkyl, said is substituted by one or more R10Substituted C1-C6C in alkyl1-C6Alkyl is C1-C4An alkyl group;
and/or when R6And R7Independently is C1-C6When alkyl, said C1-C6Alkyl is C1-C4An alkyl group;
and/or when R11Is C6-C10When aryl, said C6-C10Aryl is phenyl or naphthyl;
and/or when R11Is C1-C6When alkyl, said C1-C6Alkyl is C1-C4An alkyl group;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 5-7 membered heterocycloalkyl;
and/or, R9Is C1-C4An alkyl group;
and/or, R10Is phenyl or naphthyl;
and/or when R8Is C6-C14When aryl is saidC6-C14Aryl is C6-C10An aryl group;
and/or when R8Is represented by one or more R13Substituted C6-C14When aryl, said is substituted by one or more R13Substituted C6-C14C in aryl6-C14Aryl is C6-C10An aryl group;
and/or when R13Is C1-C6At alkoxy, said C1-C6Alkoxy is C1-C4An alkoxy group;
and/or, when said R is14Is represented by one or more R16Substituted C6-C14When aryl, said is substituted by one or more R16Substituted C6-C14C in aryl6-C14Aryl is C6-C10An aryl group;
and/or, said X4Is fluorine, chlorine, bromine or iodine;
and/or, when said R is15When independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
14. The use according to claim 13,
when R is6And R7Independently by one or more R9Substituted C6-C14When aryl, said is substituted by one or more R9Substituted C6-C14C in aryl6-C14Aryl is phenyl or naphthyl;
and/or when R6And R7Independently is C6-C14When aryl, said C6-C14Aryl is phenyl or naphthyl;
and/or when R6And R7Independently by one or more R10Substituted C1-C6When alkyl, said is substituted by one or more R10Substituted C1-C6C in alkyl1-C6Alkyl radicalIs methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R6And R7Independently is C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R11Is C6-C10When aryl, said C6-C10Aryl is phenyl;
and/or when R11Is C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 6 membered heterocycloalkyl;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the rest heteroatoms in the 3-8 membered heterocycloalkyl are oxygen;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the number of the other heteroatoms in the 3-8 membered heterocycloalkyl is 1;
and/or, R9Is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or, R10Is phenyl;
and/or when R8Is C6-C14When aryl, said C6-C14Aryl is phenyl or naphthyl;
and/or when R8Is represented by one or more R13Substituted C6-C14When aryl, said is substituted by one or more R13Substituted C6-C14C in aryl6-C14Aryl is phenyl or naphthyl;
and/or when R13Is C1-C6At alkoxy, said C1-C6Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy;
and/or, when said R is14Is represented by one or more R16Substituted C6-C14When aryl, said is substituted by one or more R16Substituted C6-C14C in aryl6-C14Aryl is phenyl or naphthyl;
and/or, said X4Is chlorine;
and/or, when said R is15When independently halogen, the halogen is chlorine.
15. The use according to claim 13,
when R is6And R7Independently by one or more R9Substituted C6-C14When aryl, said is substituted by one or more R9Substituted C6-C14C in aryl6-C14Aryl is phenyl;
and/or when R6And R7Independently is C6-C14When aryl, said C6-C14Aryl is phenyl;
and/or when R6And R7Independently by one or more R10Substituted C1-C6When alkyl, said is substituted by one or more R10Substituted C1-C6C in alkyl1-C6Alkyl is methyl;
and/or when R6And R7Independently is C1-C6When alkyl, said C1-C6Alkyl is methyl;
and/or when R11Is C1-C6When alkyl, said C1-C6Alkyl radicalIs methyl;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 5-7 membered heterocycloalkyl, and the rest heteroatoms in the 5-7 membered heterocycloalkyl are oxygen;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 5-7 membered heterocycloalkyl, and the number of the rest heteroatoms in the 5-7 membered heterocycloalkyl is 1;
and/or, R9Is methyl;
and/or when R8Is represented by one or more R13Substituted C6-C14When aryl, said is substituted by one or more R13Substituted C6-C14C in aryl6-C14Aryl is phenyl;
and/or when R13Is C1-C6At alkoxy, said C1-C6Alkoxy is methoxy;
and/or, when said R is14Is represented by one or more R16Substituted C6-C14When aryl, said is substituted by one or more R16Substituted C6-C14C in aryl6-C14Aryl is phenyl.
16. The use according to claim 14,
when R is6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 6 membered heterocycloalkyl, and the rest heteroatoms in the 6 membered heterocycloalkyl are oxygen;
and/or when R6And R7And the above R6And R7When the nitrogen atom between the two forms 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is 6 membered heterocycloalkyl, and the number of the remaining heteroatoms in the 6 membered heterocycloalkyl is 1.
17. The use according to claim 12,
R6and R7Independently hydrogen, by one or more R9Substituted C6-C14Aryl radical, C6-C14Aryl radicals, substituted by one or more R10Substituted C1-C6Alkyl radical, C1-C6Alkyl or-C (═ O) R11(ii) a Or, R6And R7And the above R6And R7Form a 3-8 membered heterocycloalkyl group with the nitrogen atom in between;
and/or, said R14Is represented by one or more R16Substituted C6-C14An aryl group;
and/or, said R15Independently is halogen;
and/or, m is 1;
and/or, said R16Is nitro.
18. The use according to any one of claims 12 to 17,
the compound shown as the formula X is
And/or, the compound shown as the formula XI is
And/or in the Buchwald-Hartwig reaction, the protective gas is nitrogen or argon;
and/or in the Buchwald-Hartwig reaction, the solvent is one or more of an alcohol solvent, an ether solvent, an amide solvent, a sulfone solvent and an aromatic hydrocarbon solvent;
and/or in the Buchwald-Hartwig reaction, the molar concentration of the compound shown in the formula X in the solvent is 0.1-2 mol/L;
and/or in the Buchwald-Hartwig reaction, the alkali is one or more of potassium carbonate, cesium carbonate, potassium phosphate, potassium sulfate, sodium hydroxide, potassium hydroxide and sodium tert-butoxide;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the alkali to the compound shown in the formula X is 1:1-2: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula I to the compound shown in the formula X is 0.001:1-0.03: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the transition metal catalyst to the compound shown in the formula X is 0.001:1-0.01: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula XI to the compound shown in the formula X is 0.1:1-2: 1;
and/or in the Buchwald-Hartwig reaction, the reaction temperature of the reaction is 80-120 ℃;
and/or in the Buchwald-Hartwig reaction, the reaction time is 0.5-20 h;
and/or the compound shown in the formula XIII is
And/or the compound shown as the formula IX is
And/or in the Suzuki reaction, the protective gas is nitrogen or argon;
and/or in the Suzuki reaction, the solvent is an ether solvent;
and/or in the Suzuki reaction, the molar concentration of the compound shown as the formula XIII in the solvent is 0.1-3 mol/L;
and/or, in the Suzuki reaction, the alkali is carbonate;
and/or in the Suzuki reaction, the molar ratio of the alkali to the compound shown in the formula XIII is 1:1-2: 1;
and/or in the Suzuki reaction, the molar ratio of the compound shown in the formula I to the compound shown in the formula XIII is 0.0001:1-0.001: 1;
and/or in the Suzuki reaction, the molar ratio of the transition metal catalyst to the compound shown in the formula XIII is 0.0001:1-0.001: 1;
and/or in the Suzuki reaction, the molar ratio of the compound shown in the formula IX to the compound shown in the formula XIII is 0.1:1-2: 1;
and/or in the Suzuki reaction, the reaction temperature of the reaction is 40-80 ℃;
and/or in the Suzuki reaction, the reaction time is 1-10 h.
19. The use according to claim 18,
in the Buchwald-Hartwig reaction, the protective gas is nitrogen;
and/or in the Buchwald-Hartwig reaction, the solvent is one or more of an alcohol solvent, an ether solvent and an aromatic hydrocarbon solvent;
and/or, in the Buchwald-Hartwig reaction, when the solvent is an alcohol solvent, the alcohol solvent is tert-butanol and/or tert-amyl alcohol;
and/or, in the Buchwald-Hartwig reaction, when the solvent is an ether solvent, the ether solvent is 1, 4-dioxane;
and/or, in the Buchwald-Hartwig reaction, when the solvent is an aromatic solvent, the aromatic solvent is toluene;
and/or in the Buchwald-Hartwig reaction, the molar concentration of the compound shown in the formula X in the solvent is 0.5-1 mol/L;
and/or in the Buchwald-Hartwig reaction, the alkali is one or more of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and sodium tert-butoxide;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the alkali to the compound shown in the formula X is 1:1-1.7: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula I to the compound shown in the formula X is 0.021:1, 0.017:1, 0.018:1, 0.016:1, 0.0027:1, 0.0034:1 or 0.0017: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the transition metal catalyst to the compound shown in the formula X is 0.01:1, 0.0087:1, 0.009:1, 0.0086:1, 0.0083:1, 0.0084:1, 0.0089:1, 0.0088:1, 0.0018:1, 0.0013:1 or 0.0085: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula XI to the compound shown in the formula X is 0.6:1-1: 1;
and/or in the Buchwald-Hartwig reaction, the reaction temperature of the reaction is 90 ℃, 100 ℃ or 110 ℃;
and/or in the Buchwald-Hartwig reaction, the reaction time is 0.5-18 h;
and/or in the Suzuki reaction, the protective gas is nitrogen;
and/or in the Suzuki reaction, the solvent is tetrahydrofuran;
and/or in the Suzuki reaction, the molar concentration of the compound shown as the formula XIII in the solvent is 1.5-2.5 mol/L;
and/or in the Suzuki reaction, the alkali is potassium carbonate;
and/or in the Suzuki reaction, the molar ratio of the alkali to the compound shown in the formula XIII is 1:1-1.5: 1;
and/or in the Suzuki reaction, the molar ratio of the compound shown in the formula I to the compound shown in the formula XIII is 0.0004: 1;
and/or in the Suzuki reaction, the molar ratio of the transition metal catalyst to the compound shown in the formula XIII is 0.0004: 1;
and/or in the Suzuki reaction, the molar ratio of the compound shown in the formula IX to the compound shown in the formula XIII is 0.6:1-1: 1;
and/or in the Suzuki reaction, the reaction temperature of the reaction is 60 ℃;
and/or in the Suzuki reaction, the reaction time is 3-6 h.
20. The use according to claim 18,
in the Buchwald-Hartwig reaction, when the solvent is an amide solvent, the amide solvent is N-methylpyrrolidone and/or N, N-dimethylacetamide;
and/or in the Buchwald-Hartwig reaction, when the solvent is a sulfone solvent, the sulfone solvent is dimethyl sulfoxide.
21. The use according to claim 18,
in the Buchwald-Hartwig reaction, the solvent is an alcohol solvent and/or an ether solvent;
and/or, in the Buchwald-Hartwig reaction, when the solvent is an alcohol solvent, the alcohol solvent is tert-amyl alcohol;
and/or in the Buchwald-Hartwig reaction, the molar concentration of the compound shown in the formula X in the solvent is 0.78mol/L, 0.76mol/L, 0.75mol/L, 0.64mol/L, 0.60mol/L, 0.63mol/L, 0.77mol/L or 0.66 mol/L;
and/or, in the Buchwald-Hartwig reaction, the alkali is cesium carbonate and/or sodium hydroxide;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the base to the compound shown in the formula X is 1.28:1, 1.32:1, 1.26:1, 1.34:1, 1.24:1, 1.2:1, 1.25:1 or 1.6: 1;
and/or in the Buchwald-Hartwig reaction, the molar ratio of the compound shown in the formula XI to the compound shown in the formula X is 0.81:1, 0.82:1, 0.84:1, 0.85:1, 0.83:1 or 0.79: 1;
and/or in the Buchwald-Hartwig reaction, the reaction time is 0.5-1h, 2h-3h, 3h-4h or 6h-18 h;
and/or in the Suzuki reaction, the molar concentration of the compound shown as the formula XIII in the solvent is 1.95 mol/L;
and/or in the Suzuki reaction, the molar ratio of the base to the compound shown in the formula XIII is 1.23: 1;
and/or in the Suzuki reaction, the molar ratio of the compound shown in the formula IX to the compound shown in the formula XIII is 0.82: 1;
and/or in the Suzuki reaction, the reaction time is 4-5 h.
22. The use according to claim 18,
in the Buchwald-Hartwig reaction, the reaction time is 1-2.5 h.
23. The use according to claim 18,
in the Buchwald-Hartwig reaction, the reaction time is 1h-1.5h or 2h-2.5 h.
24. A compound shown as a formula II in the specification,
wherein R is1、R2And R3As defined in any one of claims 1 to 6.
25. The compound of formula II according to claim 24, wherein
The compound shown as the formula II is
26. A crystalline form of a compound represented by the formula, wherein the crystal is a monoclinic crystal having a space group of P2(1)/c and unit cell parameters:
α＝90°，
β＝111.47(3)°，
γ 90 °, Z4, unit cell volume
27. A crystalline form of a compound as shown below, wherein the crystal is a triclinic crystal having a space group P2(1)/c and unit cell parameters:
α＝77.51(2)°，
β＝87.64(2)°，
γ 80.14(2) °, Z2, unit cell volume
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