CN114632552B - Buchwald pre-catalyst, preparation method and application thereof - Google Patents
Buchwald pre-catalyst, preparation method and application thereof Download PDFInfo
- Publication number
- CN114632552B CN114632552B CN202210542048.XA CN202210542048A CN114632552B CN 114632552 B CN114632552 B CN 114632552B CN 202210542048 A CN202210542048 A CN 202210542048A CN 114632552 B CN114632552 B CN 114632552B
- Authority
- CN
- China
- Prior art keywords
- solvent
- reaction
- occurrence
- butyl
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000012041 precatalyst Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 94
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 51
- -1 cinnamyl palladium chloride dimer Chemical class 0.000 claims abstract description 49
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 39
- 239000003446 ligand Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 30
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000006267 biphenyl group Chemical group 0.000 claims abstract description 14
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 13
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 9
- ZMPSAJZWHPLTKH-HYTOEPEZSA-L (e)-but-2-ene;chloropalladium(1+) Chemical compound [Pd+]Cl.[Pd+]Cl.C\C=C\[CH2-].C\C=C\[CH2-] ZMPSAJZWHPLTKH-HYTOEPEZSA-L 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 239000007790 solid phase Substances 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 4
- 239000008096 xylene Substances 0.000 claims abstract description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 238000006880 cross-coupling reaction Methods 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 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 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 10
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 239000010970 precious metal Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000005259 measurement Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- 239000003054 catalyst Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 12
- 229910052698 phosphorus Inorganic materials 0.000 description 12
- 239000011574 phosphorus Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- QHYYXPLERUSFAV-UHFFFAOYSA-N hydron;2-phenylaniline;chloride Chemical compound [Cl-].[NH3+]C1=CC=CC=C1C1=CC=CC=C1 QHYYXPLERUSFAV-UHFFFAOYSA-N 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000006555 catalytic reaction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
- NONLYMJHKGQHLQ-UHFFFAOYSA-N CS(O)(=O)=O.NC1=CC=CC=C1C1=CC=CC=C1 Chemical group CS(O)(=O)=O.NC1=CC=CC=C1C1=CC=CC=C1 NONLYMJHKGQHLQ-UHFFFAOYSA-N 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JJSHIQGDCHGCPC-UHFFFAOYSA-N CS([O-])(=O)=O.C[NH2+]c1ccccc1-c1ccccc1 Chemical compound CS([O-])(=O)=O.C[NH2+]c1ccccc1-c1ccccc1 JJSHIQGDCHGCPC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- CARILLOXVAEKID-UHFFFAOYSA-N n-methyl-2-phenylaniline Chemical group CNC1=CC=CC=C1C1=CC=CC=C1 CARILLOXVAEKID-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical group NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 239000012391 XPhos Pd G2 Substances 0.000 description 1
- CWRYPZZKDGJXCA-UHFFFAOYSA-N acenaphthene Chemical compound C1=CC(CC2)=C3C2=CC=CC3=C1 CWRYPZZKDGJXCA-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 150000001987 diarylethers Chemical class 0.000 description 1
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- ZTYYDUBWJTUMHW-UHFFFAOYSA-N furo[3,2-b]furan Chemical compound O1C=CC2=C1C=CO2 ZTYYDUBWJTUMHW-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical compound C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- ONCNIMLKGZSAJT-UHFFFAOYSA-N thieno[3,2-b]furan Chemical compound S1C=CC2=C1C=CO2 ONCNIMLKGZSAJT-UHFFFAOYSA-N 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
- B01J31/2457—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings, e.g. Xantphos
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
- C07F15/0066—Palladium compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a Buchwald pre-catalyst, a preparation method and application thereof. The preparation method comprises the following steps: mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first step of reaction is finished, adding quaternary ammonium salt containing biphenyl groups to carry out a second step of reaction; after the second step reaction is finished, adding a second solvent, separating out solid, carrying out solid-liquid separation, and retaining a solid phase; wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer; the first solvent is toluene and/or xylene; the second solvent is n-hexane and/or diethyl ether. The preparation method has the advantages of simple process, low precious metal loss, high product yield, low solvent residue of the prepared pre-catalyst finished product, high catalytic activity and accurate measurement.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a Buchwald pre-catalyst, a preparation method and application thereof.
Background
The cross-coupling reaction refers to the reaction of RX with a non-transition metal organic compound R ' M ' to form a carbon-carbon bond (R-R ') under the catalysis of a transition metal. The cross-coupling reaction has high efficiency, good selectivity and mild reaction conditions, and occupies a significant position in modern organic synthesis. Palladium catalysts are a class of catalysts widely used in cross-coupling reactions, and in order to control reaction rates, regioselectivities and stereoselectivities of different reactions, a series of ligands are often introduced into the palladium catalysts to achieve adjustability of the palladium catalysts. Currently, phosphine ligand derived palladium precatalysts, typically represented by ligand derived palladium catalyst precursors such as Buchwald precatalysts (dialkylarylphosphines, trialkylphosphines, triarylmono/bisphosphines, etc.), are used to form C-C, C-N, C-O, C-F, C-CF due to their higher stability and reactivity 3 And C-S bond, and the reactions can be carried out under mild alkaline conditions, thus having wide application prospect.
However, in the conventional technology, the preparation method of the Buchwald pre-catalyst is complex, the loss of noble metals is high, the product yield is low, and the prepared pre-catalyst finished product often has solvent residues, which easily causes misjudgment on the catalytic reaction metering and influences the catalytic activity.
Disclosure of Invention
Based on the above, the Buchwald precatalyst and the preparation method and application thereof are needed to be provided, the preparation method has the advantages of simple process, low precious metal loss, high product yield, low solvent residue of the prepared precatalyst finished product, high catalytic activity and accurate metering, the defects of the preparation method of the Buchwald precatalyst in the traditional technology can be effectively overcome, and the quality of the precatalyst finished product is improved.
In one aspect of the present invention, there is provided a method for preparing a Buchwald pre-catalyst, comprising the steps of:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first-step reaction is finished, adding quaternary ammonium salt containing biphenyl groups to perform a second-step reaction; after the second step of reaction is finished, adding a second solvent, separating out a solid, carrying out solid-liquid separation, and retaining a solid phase;
wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer, and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether.
In another aspect of the present invention, there is also provided a Buchwald precatalyst, which is prepared by the preparation method according to any one of the previous embodiments.
In another aspect of the invention, the use of the aforementioned Buchwald precatalyst in cross-coupling reactions is also provided.
The Buchwald precatalyst can be directly prepared by adopting one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer as a palladium source and reacting the palladium source with phosphine ligand and quaternary ammonium salt containing biphenyl groups through a one-pot method, has the advantages of simple and convenient process flow, few steps, mild reaction conditions, contribution to industrial amplification production and less loss, avoids noble metal loss caused by the need of separating a cyclic palladium intermediate in the traditional method, and greatly reduces the production cost; in addition, the scheme of the invention also optimizes a palladium source and a solvent, avoids the harsh requirement on the quality of the palladium acetate source in the traditional technology, does not use solvents such as tetrahydrofuran, dichloromethane and the like which are easy to coordinate with the product, and effectively reduces the residue of the solvent in the finished catalyst product.
The Buchwald pre-catalyst prepared by the invention has low solvent residue and small influence of a palladium source on the quality of a finished product, and the finished product has higher catalytic activity and more accurate catalytic reaction metering compared with the Buchwald pre-catalyst prepared by the traditional technology, can effectively improve the efficiency of cross coupling reaction, and promotes the further development of the field.
Drawings
FIG. 1 shows the NMR spectrum of the precatalyst obtained in example 1 ( 1 HNMR);
FIG. 2 shows the NMR phosphorus spectrum of the precatalyst obtained in example 1 31 PNMR);
FIG. 3 is a NMR spectrum of the precatalyst obtained in example 2: ( 1 HNMR);
FIG. 4 shows the NMR phosphorus spectrum of the pre-catalyst obtained in example 2: ( 31 PNMR);
FIG. 5 is a NMR spectrum of the precatalyst obtained in example 3: ( 1 HNMR);
FIG. 6 shows the NMR phosphorus spectrum of the pre-catalyst obtained in example 3 31 PNMR);
FIG. 7 is a NMR spectrum of the precatalyst obtained in example 4: ( 1 HNMR);
FIG. 8 shows the NMR phosphorus spectrum of the precatalyst obtained in example 4: ( 31 PNMR);
FIG. 9 is a NMR spectrum of the precatalyst obtained in example 5: ( 1 HNMR);
FIG. 10 shows the NMR phosphorus spectrum of the precatalyst obtained in example 5: ( 31 PNMR);
FIG. 11 is a NMR chart of the precatalyst obtained in example 6( 1 HNMR);
FIG. 12 is a NMR phosphorus spectrum of the precatalyst obtained in example 6: ( 31 PNMR);
FIG. 13 is a NMR spectrum of a precatalyst obtained in example 7: ( 1 HNMR);
FIG. 14 shows the NMR phosphorus spectrum of the precatalyst obtained in example 7: ( 31 PNMR);
FIG. 15 is a NMR spectrum of the precatalyst obtained in example 8: ( 1 HNMR);
FIG. 16 is a NMR phosphorus spectrum of the precatalyst obtained in example 8: ( 31 PNMR);
FIG. 17 is a NMR spectrum of the precatalyst obtained in example 9: ( 1 HNMR);
FIG. 18 shows the NMR phosphorus spectrum of the precatalyst obtained in example 9 31 PNMR);
FIG. 19 is a NMR spectrum of the precatalyst obtained in example 10: ( 1 HNMR);
FIG. 20 shows the NMR phosphorus spectrum of the precatalyst obtained in example 10: ( 31 PNMR);
FIG. 21 is a NMR chart of the precatalyst obtained in example 11: ( 1 HNMR);
FIG. 22 is a NMR phosphorus spectrum of the precatalyst obtained in example 11: ( 31 PNMR);
FIG. 23 is a nuclear magnetic resonance hydrogen spectrum of an intermediate obtained in step (1) of comparative example 1: ( 1 HNMR);
FIG. 24 shows the NMR phosphorus spectrum of the intermediate obtained in step (1) of comparative example 1 31 PNMR)。
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless specifically limited otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, the numerical intervals are regarded as continuous, and include the minimum and maximum values of the range and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
The percentage contents referred to in the present invention mean, unless otherwise specified, mass percentages for solid-liquid mixing and solid-solid phase mixing, and volume percentages for liquid-liquid phase mixing.
The percentage concentrations referred to in the present invention are, unless otherwise specified, the final concentrations. The final concentration refers to the ratio of the additive component in the system to which the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C 1 ~C 6 Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms, which may be independently at each occurrence C 1 Alkyl radical, C 2 Alkyl radical, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl or C 6 An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et-CH) 2 CH 3 ) 1-propyl group (b)n-Pr、n-propyl, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl group (b)i-Pr、i-propyl, isopropyl, -CH (CH) 3 ) 2 ) 1-butyl group (b)n-Bu、n-butyl, -CH 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl group (c) ((r))i-Bu、i-butyl, -CH 2 CH(CH 3 ) 2 ) 2-butyl group (b)s-Bu、s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl group(s) ((s))t-Bu、t-butyl, -C (CH) 3 ) 3 ) 1-pentyl group(s) ((s))n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) And 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 。
The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing ring carbon atoms and may be a monocycloalkyl, or spirocycloalkyl, or bridged cycloalkyl. Phrases containing the term, e.g., "C 3 ~C 6 Cycloalkyl "refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which may be independently C 3 Cycloalkyl radical, C 4 Cycloalkyl radical, C 5 Cycloalkyl or C 6 A cycloalkyl group. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclo and cyclohexyl (Cy). In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl groups containing a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.
The term "alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C 1 ~C 6 Alkoxy "means that the alkyl moiety contains 1 to 6 carbon atoms and, at each occurrence, may be independently C 1 Alkoxy radical, C 4 Alkoxy radical, C 5 Alkoxy or C 6 An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH) 2 CH 3 or-OEt) and tert-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
"aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from the aromatic ring compound and may be a monocyclic aryl group, or a fused ring aryl group, or a polycyclic aryl group, at least one of which is an aromatic ring system for polycyclic ring species. For example, "C 5 ~C 20 Aryl "refers to an aryl group containing 5 to 20 carbon atoms, which at each occurrence, independently of each other, can be C 5 Aryl radical, C 6 Aryl radical, C 10 Aryl radical, C 14 Aryl radical, C 18 Aryl or C 20 And (4) an aryl group. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof. It will be appreciated that multiple aryl groups may also be interrupted by short non-aromatic units (e.g. by short non-aromatic units)<10% of atoms other than H, such as C, N or O atoms), such as in particular acenaphthene, fluorene, or 9, 9-diarylfluorene, triarylamine, diaryl ether systems should also be included in the definition of aryl.
"heteroaryl" means that on the basis of an aryl at least one carbon atom is replaced by a non-carbon atom which may be a N atom, an O atom, an S atom, etc. For example, "C 3 ~C 10 Heteroaryl "refers to a heteroaryl group containing 3 to 10 carbon atoms, which at each occurrence may be independently C 3 Heteroaryl group, C 4 Heteroaryl group, C 5 Heteroaryl group, C 6 Heteroaryl group, C 7 Heteroaryl or C 8 A heteroaryl group. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, primadine, quinazoline, and quinazolinone.
"bonded to form a ring or not" means that the two groups may be independently presentThe ring structure may be formed together with the surrounding atoms by a chemical bond. The bonding to the ring may be, for example, to form a five-membered ring, a six-membered ring or a seven-membered ring, and the ring forming species may be, for example, a cycloalkane, an aromatic ring or a heteroaromatic ring. For example,wherein R ' and R ' ' may form a ring(cyclohexane condensed with benzene ring formed by bonding two ethyl groups on benzene ring),(1, 3-dioxolane fused with a benzene ring formed by bonding one methoxy group and one hydroxyl group on the benzene ring),(1, 4-dioxane fused with benzene ring is formed by bonding two methoxy groups on benzene ring) or(two vinyl groups on the benzene ring are bonded to form a benzene ring fused with the benzene ring).
"non-reactive gas" means a gas which does not participate in the reaction of the reaction system, and may be, for example, nitrogen, argon or other inert gas.
In one aspect of the present invention, there is provided a method for preparing a Buchwald pre-catalyst, comprising the steps of:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first step of reaction is finished, adding quaternary ammonium salt containing biphenyl groups to carry out a second step of reaction; after the second step reaction is finished, adding a second solvent, separating out solid, carrying out solid-liquid separation, and retaining a solid phase;
wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether.
At present, researchers have developed multiple generations of Buchwald pre-catalysts, and four more mature generations of Buchwald pre-catalysts exist. Among these, the deprotonation of the first generation (G1) precatalyst under basic conditions enables the generation of the active Pd (0) species and the resulting catalyst activity is very high. Even at low temperatures of-40 ℃, various cross-coupling reactions can still occur. The second generation (G2) precatalyst replaced the phenethylamine backbone in the (G1) complex with a biphenyl ligand, an improvement that allowed researchers to generate active Pd species at room temperature using weak phosphates or carbonates, and the second generation (G2) catalyst was significantly more conducive to accelerating large numbers of Suzuki-Miyaura couplings in other cross-coupling reactions. The versatility of third generation (G3) precatalysts is the greatest compared to the first two, are highly soluble in a variety of common organic solvents, are able to accommodate a large number of ligands, such as the BrettPhos family, and their efficacy in solution is also significantly extended. In some special cases, carbazole leaving groups may inhibit the catalytic reaction, and to avoid this problem, the Buchwald group prepared a G4 precatalyst on the basis of a G3 precatalyst by methylating the amino group on the biphenyl backbone. It has higher solubility in cross-coupling reaction, and retains the excellent catalytic activity of G3 catalyst.
At present, the G2-G4 catalyst containing biphenyl groups is mainly prepared by the following method:
g2: o-aminobiphenyl forms corresponding salt with trimethylchlorosilane under proper conditions, and the salt is treated with Pd (OAc) 2 The cyclic palladium dimer is obtained through reaction, and the cyclic palladium dimer further reacts with the ligand to obtain the needed precatalyst.
G3: o-aminobiphenyl forms a corresponding salt with MsOH under appropriate conditions, and the salt is treated with Pd (OAc) 2 The cyclic palladium dimer is obtained through reaction, and the cyclic palladium dimer further reacts with the ligand to obtain the needed precatalyst.
G4: adding solvent, o-aminobiphenyl, dropwise adding n-BuLi into ice salt bath, stirring for 1h after dropwise adding, and adding CH 3 I, after complete reaction, carrying out post-treatment to obtain N-methyl-2-aminobiphenyl; adding N-methyl-2-aminobiphenyl and MsOH under proper conditions to form salt in a corresponding solvent, and adding Pd (OAc) after the reaction is completed 2 The reaction is complete, the required target compound is obtained after post treatment, and the cyclic palladium dimer further reacts with the ligand to obtain the required pre-catalyst.
Therefore, in the traditional methods, palladium acetate is basically used as a palladium source, however, polymeric palladium acetate or nitrogen-containing palladium acetate has a significant influence on the product quality and yield, so that the preparation methods have high requirements on the quality of the palladium acetate source, and if the quality of the palladium source does not meet the requirements, a high-quality pre-catalyst is difficult to prepare. In addition, the methods need to form a cyclic palladium intermediate, and the next reaction can be carried out after separation, so that the loss of noble metals is easily caused, the operation is complex and time-consuming, and the production cost is greatly increased. Furthermore, these processes often use tetrahydrofuran or dichloromethane as solvent, and both of these solvents are very easily coordinated with palladium, so that a large amount of residues remain in the finished product of the pre-catalyst, which affects the reactivity and accuracy of the catalytic reaction metering.
In order to solve the problems in the prior art, the researchers of the invention discover through a great deal of research that the Buchwald pre-catalyst can be directly prepared by adopting one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer as a palladium source and reacting the palladium source with phosphine ligand and quaternary ammonium salt containing biphenyl groups through a one-pot method, the process flow is simple and convenient, the steps are few, the reaction condition is mild, the industrial amplification production is facilitated, the loss is low, the precious metal loss caused by the separation of a cyclic palladium intermediate in the traditional method is avoided, and the production cost is greatly reduced; in addition, the scheme of the invention also optimizes a palladium source and a solvent, avoids the harsh requirement on the quality of the palladium acetate source in the traditional technology, does not use solvents such as tetrahydrofuran, dichloromethane and the like which are easy to coordinate with the product, and effectively reduces the residue of the solvent in the finished catalyst product.
In some embodiments, the reaction temperature of the first step reaction is 5 ℃ to 25 ℃. Preferably, the temperature of the first step reaction is 10 ℃ to 15 ℃. The reaction temperature of the first step reaction is controlled within a proper range, so that the reaction is kept efficient, and the intermediate is not decomposed to form a simple substance palladium byproduct due to the excessively high reaction speed.
It will be appreciated that the first step reaction may be monitored by monitoring means conventional in the art, for example by HPLC (high performance liquid chromatography) or GC (gas chromatography). In particular, can be prepared by 31 P is monitored until the peak of the phosphine ligand is completely disappeared, indicating that the reaction has proceeded completely.
In some embodiments, the reaction temperature of the second step reaction is 20 ℃ to 30 ℃. Preferably, the temperature of the second reaction is 25 ℃. The reaction temperature of the second step is controlled within a suitable range, so that the reaction can be completed without causing decomposition of the intermediate.
In some embodiments, the time of the second step reaction is 10 h to 14 h, preferably 12 h.
In some embodiments, the second solvent is added and stirred for 20 min to 40 min to precipitate a solid, preferably for 30 min.
In some embodiments, the solid-liquid separation is maintained anhydrous and oxygen free. Preferably, after the solid-liquid separation is completed, the solid phase is washed with the second solvent.
In some embodiments, the resulting solid phase is subjected to vacuum extraction to remove residual solvent.
Preferably, the second solvent is n-hexane. The n-hexane is used as a poor solvent to separate out the pre-catalyst, and compared with the ether, the pre-catalyst is not easy to coordinate with the ether, so that the solvent residue in a finished product is less, and the quality is higher.
In some embodiments, the ratio of the amounts of the palladium source, the phosphine ligand, and the quaternary ammonium salt having a biphenyl group is 1 (2-2.5) to (2-2.5). The ratio of the amounts of the palladium source, the phosphine ligand and the quaternary ammonium salt containing a biphenyl group may also be, for example, 1: 2.1: 2.1, 1: 2.1: 2.2, 1: 2.1: 2.3, 1: 2.1: 2.4, 1: 2.2: 2.1, 1: 2.2: 2.2, 1: 2.2: 2.3, 1: 2.2: 2.4, 1: 2.3: 2.1, 1: 2.3: 2.2, 1: 2.3: 2.3, 1: 2.3: 2.4, 1: 2.4: 2.1, 1: 2.4: 2.2, 1: 2.4: 2.3 or 1: 2.4: 2.4. The ratio of the three substances is controlled within a proper range, so that the reaction can be carried out more thoroughly; preferably, the ratio of the three substances is 1 (2-2.1) to 2-2.1, which not only allows the reaction to proceed completely, but also reduces the cost.
In some embodiments, the amount of the palladium source is 0.5 mol to 1mol per 1L of the first solvent. The amount of the palladium source used may be, for example, 0.6 mol, 0.7 mol, 0.8 mol, or 0.9 mol per 1L of the first solvent. The concentration of the palladium source in the solvent is controlled within a proper range, so that the reaction rate of the first step is moderate, and the intermediate product is better generated.
In some embodiments, the volume ratio of the first solvent to the second solvent is 1 (2-5). The volume ratio of the first solvent to the second solvent may also be, for example, 1:2.5, 1:3, 1:3.5, 1:4, or 1: 4.5. The volume ratio of the first solvent to the second solvent is controlled in a proper range, so that the pre-catalyst can be completely precipitated and has small loss, and no more waste liquid is generated.
In some embodiments, the phosphine ligand has a structure according to any one of formulas I-IV:
wherein m is 1, 2,3 or 4;
n is 1, 2,3, 4 or 5;
R 1 ~R 13 each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 -CN, halogen, adamantyl, unsubstituted or R 19 Substituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted or R 20 Substituted C 3 ~C 6 Cycloalkyl, unsubstituted or R 21 Substituted C 5 ~C 20 Aryl, unsubstituted or R 22 Substituted C 3 ~C 10 A heteroaryl group;
preferably, R 1 ~R 13 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, adamantyl, unsubstituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted C 3 ~C 6 Cycloalkyl, unsubstituted C 5 ~C 10 Aryl, unsubstituted C 3 ~C 5 A heteroaryl group;
further preferably, R 1 ~R 13 Each occurrence is independently selected from-H, -NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl or pyridyl;
even more preferably, R 1 ~R 13 Each occurrence is independently selected from-H, -NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, isopropyl, n-butyl, t-butyl, methoxy, isopropoxy, cyclohexyl, phenyl or furanyl.
R 14 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 -CN, halogen, adamantyl, unsubstituted or R 19 Substituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted or R 20 Substituted C 3 ~C 6 Cycloalkyl, unsubstituted or R 21 Substituted C 5 ~C 20 Aryl, unsubstituted or R 22 Substituted C 3 ~C 10 Heteroaryl, -PR 23 R 24 ;
Preferably, R 14 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, adamantyl, unsubstituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted C 3 ~C 6 Cycloalkyl radicals, toSubstituted C 5 ~C 10 Aryl, unsubstituted C 3 ~C 5 Heteroaryl or-PR 23 R 24 ;
Further preferably, R 14 Each occurrence is independently selected from-H, -NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl, pyridyl or-PR 23 R 24 ;
Even more preferably, R 14 Each occurrence is independently selected from-H, -NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, isopropyl, n-butyl, t-butyl, methoxy, isopropoxy, cyclohexyl, phenyl, furyl or-PR 23 R 24 ;
R 15 ~R 18 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R 15 And R 16 、R 16 And R 17 、R 17 And R 18 Independently bonding to form a ring or not to form a ring;
preferably, R 15 ~R 18 Each occurrence is independently selected from-H, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R is 15 And R 16 、R 16 And R 17 、R 17 And R 18 Independently bonding to form a ring or not to form a ring;
further preferably, R 15 ~R 18 Each occurrence is independently selected from-H, -Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butylVinyl, hydroxy or methoxy, and R 15 And R 16 、R 16 And R 17 、R 17 And R 18 Independently bonded to form a ring or not.
In some embodiments, R 15 And R 16 、R 16 And R 17 、R 17 And R 18 Are not bonded into a ring.
In some embodiments, R 15 And R 16 、R 16 And R 17 、R 17 And R 18 Are respectively and independently bonded to form a five-membered ring or a six-membered ring.
A is independently selected from the group consisting of a single bond, -O-, -NH-, -C (= O) -, CR, for each occurrence 25 R 26 Or is absent;
preferably, A is independently selected for each occurrence from the group consisting of-O-, -NH-, and CR 25 R 26 Or is absent.
R 19 ~R 26 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, methyl, ethyl, methoxy, cyclohexyl or phenyl.
Preferably, R 19 ~R 26 Each occurrence is independently selected from-H, -CF 3 -Br, -Cl, methyl, ethyl, methoxy, cyclohexyl or phenyl.
In some embodiments, the phosphine ligand is selected from one or more of the following compounds:
in the above-listed phosphine ligands, the racemic structure also includes chiral versions of the phosphine ligands, e.g., L25 includes racemic L25 itself,and。
in some embodiments, the quaternary ammonium salt containing biphenyl groups has the structure shown in formula V:
wherein p is 1, 2,3 or 4;
q is 1, 2,3, 4 or 5;
X - is selected from F - 、Cl - 、Br - 、I - Or OMs - ;
R 27 ~R 28 Each occurrence is independently selected from-H, -D, methyl, ethyl, or methoxy;
preferably, R 27 ~R 28 Each occurrence is independently selected from-H or methyl.
Wherein, OMs - Refers to methylsulfonate.
R 29 ~R 30 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl.
Preferably, the first and second electrodes are formed of a metal,R 29 ~R 30 each occurrence is independently selected from-H, -NMe 2 Halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or methoxy.
Even more preferably, R 29 ~R 30 Is selected from-H.
In some embodiments, the quaternary ammonium salt containing a biphenyl group is selected from one or more of the following compounds:
in another aspect of the present invention, there is also provided a Buchwald precatalyst, which is prepared by the preparation method according to any one of the previous embodiments.
The Buchwald pre-catalyst prepared by the invention has low solvent residue and small influence of a palladium source on the quality of a finished product, and the finished product has higher catalytic activity and more accurate catalytic reaction metering compared with the Buchwald pre-catalyst prepared by the traditional technology, can effectively improve the efficiency of cross coupling reaction, and promotes the further development of the field.
In another aspect of the invention, the use of the aforementioned Buchwald precatalyst in cross-coupling reactions is also provided.
The present invention will be described in further detail with reference to specific examples and comparative examples. Experimental parameters not described in the following specific examples are preferably referred to the guidelines given in the present application, and may be referred to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by the manufacturer. It is understood that the following examples are specific to the particular apparatus and materials used, and in other embodiments, are not limited thereto; the weight of the related components mentioned in the embodiments of the present specification may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the embodiments of the present specification according to the present specification. Specifically, the weight described in the description of the embodiment of the present invention may be a mass unit known in the chemical engineering field such as μ g, mg, g, kg, etc.
And (3) reagent sources:
allyl palladium chloride dimer, crotyl palladium chloride dimer, cinnamyl palladium chloride dimer and palladium acetate were purchased from the noble platinum industry, and the other reagents were analytically pure.
Example 1
(1)Ar 2 Adding allyl palladium chloride dimer (36.6g,0.1mol), L18 (71.7g,0.2mol) and 183 ml of toluene into a 1L three-neck flask under the atmosphere, stirring at 10-15 ℃, continuously releasing allyl chloride gas along with the continuous reaction, gradually turning yellow precipitate into white, and reacting in the process of reaction by 31 P monitoring until the peak of phosphine ligand completely disappeared;
(2) adding 2-aminobiphenyl hydrochloride (41.1 g,0.2mol) into the reaction system with the phosphine ligand peak completely disappeared in the step (1), stirring for 12h at 25 ℃, then adding 366 ml of n-hexane, stirring for 30min, filtering without water and oxygen, washing with n-hexane, and vacuum-drying the solvent to obtain Ad 2 P(n-Bu) Pd G2 precatalyst as an off-white powder (128.2G, 95.9% yield).
Example 2
Substantially the same as in example 1 except that the palladium source in step (1) was replaced with crotyl palladium chloride dimer in an equivalent amount to that of product Ad 2 P(n-Bu) Pd G2 precatalyst as an off-white powder (125.0G, 93.5% yield).
Example 3
Essentially the same as in example 1, except that the palladium source in step (1) was replaced with an equivalent amount of cinnamyl palladium chloride dimer, product Ad 2 P(n-Bu) Pd G2 precatalyst as an off-white powder (125.8G, 94.1% yield).
Example 4
Substantially the same as in example 1 except that 2-aminobiphenyl hydrochloride in step (2) was replaced with 2-aminobiphenyl methanesulfonate in an equivalent amount to that of product Ad 2 P(n-Bu) Pd G3 catalyst was an off-white powder (137.9g, yield 94.7%).
Example 5
Essentially the same as in example 1, except that in step (2) the 2-aminobiphenyl hydrochloride was replaced with an equivalent amount of 2-methylaminobiphenyl methanesulfonate, product Ad 2 P(n-Bu) Pd G4 catalyst was an off-white powder (138.4G, 93.2% yield).
Example 6
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L5, the product XPhos Pd G2 catalyst was an off-white powder (152.8G, 97.2% yield).
Example 7
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L3, the 2-aminobiphenyl hydrochloride in step (2) was replaced with an equivalent amount of 2-aminobiphenyl methanesulfonate, and the product SPhos Pd G3 catalyst was an off-white powder (150.3G, 96.3% yield).
Example 8
Substantially the same as in example 7 except that the phosphine ligand in step (1) was replaced with L11 in an equivalent amount, the productt-Bu 3 The Pd G3 catalyst was an off-white powder (105.3G, 92% yield).
Example 9
Essentially the same as example 1 except that in step (1) the phosphine ligand was replaced by equivalent amounts of L20, in step (2) the 2-aminobiphenyl hydrochloride was replaced by equivalent amounts of 2-methylaminobiphenyl methane sulfonate, and the product Xantphos Pd G4 catalyst was an off-white powder (187.3G, 97.3% yield).
Example 10
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L13, the 2-aminobiphenyl hydrochloride in step (2) was replaced with an equivalent amount of 2-aminobiphenyl methanesulfonate, and the product P (o-tol)3 Pd G3 catalyst was an off-white powder (126.9G, 94.1% yield).
Example 11
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with L27 in an equivalent amount, the 2-aminobiphenyl hydrochloride in step (2) was replaced with 2-aminobiphenyl methanesulfonate in an equivalent amount, and the product BINAP Pd G3 catalyst was an off-white powder (193.5G, 97.5% yield).
Comparative example 1
(1)Ar 2 Adding allyl palladium chloride dimer (36.6g,0.1mol), L18 (71.7g,0.2mol) and 183 ml of toluene into a 1L three-neck flask under the atmosphere, stirring at 10-15 ℃, continuously releasing allyl chloride gas along with the continuous reaction, gradually turning yellow precipitate into white, and reacting in the process of reaction by 31 Monitoring P until the peak of the phosphine ligand completely disappears, adding 366 ml of n-hexane for anhydrous and oxygen-free filtration, and performing vacuum drying to obtain a light yellow powder intermediate;
(2)Ar 2 adding the light yellow powder intermediate prepared in the step (1) and 2-aminobiphenyl hydrochloride (41.1 g,0.2mol) into a 1L three-neck flask under the atmosphere, stirring for 12h at 25 ℃, then adding 366 ml of n-hexane, stirring for 30min, carrying out anhydrous and oxygen-free filtration, washing with n-hexane, and carrying out vacuum drying on the solvent to obtain Ad 2 P(n-Bu) Pd G2 precatalyst as an off-white powder (121.0G, yield 90.5%).
Comparative example 2
Substantially the same as in example 1 except that the reaction temperature in step (1) was 30 ℃. In this comparative example, in step (1), due to the excessively high temperature, the formation of a black elemental palladium by-product in the system was observed, which significantly decreased the yield.
Comparative example 3
Substantially the same as in example 1 except that the palladium source was replaced with palladium acetate in an equivalent amount in step (1). In the comparative example, the boiling point of acetic acid is high, so that the process cannot be removed and the off-white reaction cannot be normally carried out.
The nuclear magnetic spectrum of each example shows that the pre-catalyst prepared by the method has high purity, less solvent residue, higher quality and more accurate catalytic reaction metering. As can be seen from the spectra (FIGS. 23 to 24) of the intermediate of comparative example 1, the intermediate can be isolated and stably exist. From the spectrograms (fig. 1-2) of the example 1, the preparation method of the invention does not need to separate the intermediate product, the one-pot two-step method can normally carry out the reaction to obtain the target product precatalyst, and the one-pot two-step method has higher yield than the comparative example 1 because the separation is not needed, thereby effectively reducing the loss of noble metals in the preparation process, simplifying the process and greatly reducing the production cost.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims, and the description and drawings can be used to explain the contents of the claims.
Claims (12)
1. A preparation method of a Buchwald pre-catalyst is characterized by comprising the following steps:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first-step reaction is finished, adding quaternary ammonium salt containing biphenyl groups to perform a second-step reaction; after the second step of reaction is finished, adding a second solvent, separating out a solid, carrying out solid-liquid separation, and retaining a solid phase;
wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer, and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether;
the reaction temperature of the first step reaction is 5-25 ℃;
the reaction temperature of the second step reaction is 20-30 ℃.
2. The method according to claim 1, wherein the ratio of the amounts of the palladium source, the phosphine ligand and the quaternary ammonium salt having a biphenyl group is 1 (2-2.5) to (2-2.5).
3. The method according to claim 1, wherein the palladium source is used in an amount of 0.5 to 1mol per 1L of the first solvent.
4. The preparation method according to claim 1, wherein the volume ratio of the first solvent to the second solvent is 1 (2-5).
5. The method according to any one of claims 1 to 4, wherein the phosphine ligand has a structure represented by any one of formulae I to IV:
wherein m is 1, 2,3 or 4;
n is 1, 2,3, 4 or 5;
R 1 ~R 13 each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 -CN, halogen, adamantyl, unsubstituted or R 19 Substituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted or R 20 Substituted C 3 ~C 6 Cycloalkyl, unsubstituted or R 21 Substituted C 6 ~C 20 Aryl, unsubstituted or R 22 Substituted C 3 ~C 10 A heteroaryl group;
R 14 each occurrence is singlyThe location is selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 -CN, halogen, adamantyl, unsubstituted or R 19 Substituted C 1 ~C 6 Alkyl or alkoxy, unsubstituted or R 20 Substituted C 3 ~C 6 Cycloalkyl, unsubstituted or R 21 Substituted C 6 ~C 20 Aryl, unsubstituted or R 22 Substituted C 3 ~C 10 Heteroaryl, -PR 23 R 24 ;
R 15 ~R 18 Each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R 15 And R 16 、R 16 And R 17 、R 17 And R 18 Independently bonding to form a ring or not to form a ring;
a is independently selected from the group consisting of a single bond, -O-, -NH-, -C (= O) -, CR, for each occurrence 25 R 26 Or is absent;
R 19 ~R 26 each occurrence is independently selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, methyl, ethyl, methoxy, cyclohexyl or phenyl.
6. The method of claim 5, wherein R is 1 ~R 13 Each occurrence is independently selected from-H, -NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl or pyridyl.
7. The method of claim 5, wherein R is 14 Each occurrence is independently selected from-H、-NMe 2 、-F、-Cl、-Br、-CF 3 Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl, pyridyl or-PR 23 R 24 。
9. the method according to any one of claims 1 to 4, wherein the quaternary ammonium salt containing a biphenyl group has a structure represented by formula V:
wherein p is 1, 2,3 or 4;
q is 1, 2,3, 4 or 5;
X - is selected from F - 、Cl - 、Br - 、I - Or OMs - ;
R 27 ~R 28 Each occurrence is independently selected from-H, -D, methyl, ethyl, or methoxy;
R 29 ~R 30 each occurrence is independentIs selected from-H, -D, -NMe 2 、-NO 2 、-CF 3 CN, -halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl.
11. a Buchwald pre-catalyst, characterized by being prepared by the preparation method of any one of claims 1 to 10.
12. Use of a Buchwald precatalyst as defined in claim 11 in cross-coupling reactions.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210542048.XA CN114632552B (en) | 2022-05-19 | 2022-05-19 | Buchwald pre-catalyst, preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210542048.XA CN114632552B (en) | 2022-05-19 | 2022-05-19 | Buchwald pre-catalyst, preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114632552A CN114632552A (en) | 2022-06-17 |
CN114632552B true CN114632552B (en) | 2022-08-02 |
Family
ID=81953069
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210542048.XA Active CN114632552B (en) | 2022-05-19 | 2022-05-19 | Buchwald pre-catalyst, preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114632552B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105801625A (en) * | 2016-05-30 | 2016-07-27 | 郑州大学 | Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction |
JP2019011286A (en) * | 2017-06-30 | 2019-01-24 | 公益財団法人相模中央化学研究所 | Phosphine compound and catalyst for coupling containing the same as ligand |
CN109400646A (en) * | 2018-12-31 | 2019-03-01 | 湖北大学 | A kind of novel B uchwald-type monophosphorus ligand and preparation method thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013184198A1 (en) * | 2012-06-08 | 2013-12-12 | Massachusetts Institute Of Technology | Phosphine-ligated palladium sulfonate palladacycles |
-
2022
- 2022-05-19 CN CN202210542048.XA patent/CN114632552B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105801625A (en) * | 2016-05-30 | 2016-07-27 | 郑州大学 | Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction |
JP2019011286A (en) * | 2017-06-30 | 2019-01-24 | 公益財団法人相模中央化学研究所 | Phosphine compound and catalyst for coupling containing the same as ligand |
CN109400646A (en) * | 2018-12-31 | 2019-03-01 | 湖北大学 | A kind of novel B uchwald-type monophosphorus ligand and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN114632552A (en) | 2022-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jin et al. | Highly Active, Well‐Defined (Cyclopentadiene)(N‐heterocyclic carbene) palladium Chloride Complexes for Room‐Temperature Suzuki–Miyaura and Buchwald–Hartwig Cross‐Coupling Reactions of Aryl Chlorides and Deboronation Homocoupling of Arylboronic Acids | |
CN110105305B (en) | Transition metal catalyzed C-H activation/cyclization synthesis 1,2-benzothiazine derivative green synthesis method | |
CN112675919B (en) | Application of N-heterocyclic carbene-based mixed nickel (II) complex in synthesis of alpha-benzyl benzofuran compound | |
WO2014077321A1 (en) | Aluminum catalyst | |
EP3559012B1 (en) | Metal organic compounds | |
CN114436949B (en) | Tetradentate ligand, metal complex, and preparation methods and applications thereof | |
CN111875515A (en) | Method for generating amide by catalyzing primary amine with metal complex | |
CN112645909A (en) | Method for synthesizing alpha-benzyl benzofuran compound | |
CN111468191A (en) | Synthetic method of ruthenium carbene catalyst | |
AU2008300526A1 (en) | Accelerated reduction of organic substances with boranes | |
CN114632552B (en) | Buchwald pre-catalyst, preparation method and application thereof | |
CN114805013B (en) | Synthesis method of halogenated biaryl compound | |
CN109232529B (en) | Preparation method of Rh (III) catalytic compound with nitrogen heterocyclic skeleton | |
Harinath et al. | NHC–Zn alkyl catalyzed cross-dehydrocoupling of amines and silanes | |
CN114989178A (en) | Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof | |
CN107935803B (en) | Synthetic method of 1, 2-diketone compound | |
JP2003522744A (en) | Method for producing polycyclic aromatic compound | |
CN109369515B (en) | Synthetic method of unsaturated double-bond substituted carbocyclic derivative | |
CN108456172B (en) | Chiral N-heterocyclic carbene precursor compound with benzimidazole skeleton and preparation method and application thereof | |
WO2017193288A1 (en) | Synthesis of phosphine ligands bearing tunable linkage: methods of their use in catalysis | |
WO2009122408A1 (en) | STABLE C - (sup3) - CYCLOMETALATED PINCER COMPLEXES, THEIR PREPARATION AND USE AS CATALYSTS | |
CN114805435B (en) | Process for preparing biaryl phosphine compounds | |
CN111732541B (en) | Method for efficiently synthesizing 6-alkenyl phenanthridine derivative through ruthenium-catalyzed C-H activation/cyclization reaction | |
CN117143158A (en) | Cyclic palladium catalyst precursor, cyclic palladium catalyst, preparation method and application | |
WO2016100101A1 (en) | Ruthenium-based metathesis pre-catalyst compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |