EP0601156A1 - Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungen - Google Patents
Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungenInfo
- Publication number
- EP0601156A1 EP0601156A1 EP93912904A EP93912904A EP0601156A1 EP 0601156 A1 EP0601156 A1 EP 0601156A1 EP 93912904 A EP93912904 A EP 93912904A EP 93912904 A EP93912904 A EP 93912904A EP 0601156 A1 EP0601156 A1 EP 0601156A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- independently
- general formula
- diyl
- radical
- compounds
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 title claims abstract description 15
- 238000006880 cross-coupling reaction Methods 0.000 title claims abstract description 12
- 235000010338 boric acid Nutrition 0.000 title abstract description 6
- 125000005619 boric acid group Chemical class 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 5
- 150000003624 transition metals Chemical class 0.000 claims abstract description 5
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 3
- -1 piperidine-1,4-diyl Chemical group 0.000 claims description 15
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 11
- 125000005620 boronic acid group Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical class 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical class 0.000 claims description 5
- 150000002366 halogen compounds Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002497 iodine compounds Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 150000007513 acids Chemical class 0.000 abstract description 3
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 abstract 1
- UYANAUSDHIFLFQ-UHFFFAOYSA-N borinic acid Chemical class OB UYANAUSDHIFLFQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000011734 sodium Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- 239000003446 ligand Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- CRCASZFDSWMENA-UHFFFAOYSA-N 4-[4-(4-propylcyclohexyl)phenyl]benzonitrile Chemical compound C1CC(CCC)CCC1C1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 CRCASZFDSWMENA-UHFFFAOYSA-N 0.000 description 4
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- QTBUVZSHCNAPRT-UHFFFAOYSA-N [4-(4-propylcyclohexyl)phenyl]boronic acid Chemical compound C1CC(CCC)CCC1C1=CC=C(B(O)O)C=C1 QTBUVZSHCNAPRT-UHFFFAOYSA-N 0.000 description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical class C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 4
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HINICOSKCHKZOG-UHFFFAOYSA-N lithium;1,2-difluorobenzene-6-ide Chemical class [Li+].FC1=CC=C[C-]=C1F HINICOSKCHKZOG-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940058905 antimony compound for treatment of leishmaniasis and trypanosomiasis Drugs 0.000 description 2
- 150000001463 antimony compounds Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229940093920 gynecological arsenic compound Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- 150000003018 phosphorus compounds Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- QXVGWYWOARYLCY-UHFFFAOYSA-N 1,2-difluoro-3-iodobenzene Chemical compound FC1=CC=CC(I)=C1F QXVGWYWOARYLCY-UHFFFAOYSA-N 0.000 description 1
- RKWWASUTWAFKHA-UHFFFAOYSA-N 1-bromo-2,3-difluorobenzene Chemical compound FC1=CC=CC(Br)=C1F RKWWASUTWAFKHA-UHFFFAOYSA-N 0.000 description 1
- YMQPKONILWWJQG-UHFFFAOYSA-N 4-bromo-1,2-difluorobenzene Chemical compound FC1=CC=C(Br)C=C1F YMQPKONILWWJQG-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 150000001495 arsenic compounds Chemical class 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 description 1
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical class OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- VNWHJJCHHGPAEO-UHFFFAOYSA-N fluoroboronic acid Chemical class OB(O)F VNWHJJCHHGPAEO-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- FFZYFXSVOADDPG-UHFFFAOYSA-N lithium;fluorobenzene Chemical compound [Li+].FC1=CC=CC=[C-]1 FFZYFXSVOADDPG-UHFFFAOYSA-N 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- VUYVXCJTTQJVKJ-UHFFFAOYSA-L palladium(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Pd]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 VUYVXCJTTQJVKJ-UHFFFAOYSA-L 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 235000019794 sodium silicate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- ZLUSCZLCHQSJRU-UHFFFAOYSA-N thallium(1+) Chemical class [Tl+] ZLUSCZLCHQSJRU-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Definitions
- the invention relates to a method for cross-coupling boronic acids with halogen compounds using a metallic palladium catalyst for the preparation of compounds of general formula I.
- R 1 and R 2 each independently of one another are an unsubstituted or at least one halogen-substituted alkyl, alkoxy or alkenyl radical having 1 to 15 carbon atoms, one or more CH 2 groups in these radicals also being each independently O-, -S-, .
- R 2 also -H, -CN, -NCS, - Cl, -F, -CF 3 , -OCF 3 , -OCF 2 H or -OC 2 F 5 , -NH 2 , -COOH, -OH or -OCH 2 Ph, A 1 , A 2 and
- a 3 each independently
- x 3 and x 4 mean independently of one another R 1 or R 2 .
- Z 1 and Z 2 each independently of one another -CO-O-, -O-CO-,
- a difluorobenzene is reacted with butyllithium or lithium diisopropylamide in the presence of trimethyl borate and in a second stage the boronic acid obtained with a difluorobromobenzene in the presence of tetrakis (triphenylphosphine) palladium - (o) and an aqueous sodium carbonate solution mixed with toluene converted into a compound according to general formula I.
- a difluorobenzene is lithiated with butyllithium at -78 ° C and then iodized at the same temperature.
- the difluoroiodobenzene obtained is then reacted with a boronic acid in the presence of tetrakis (triphenylphosphine) palladium - (O) and an aqueous sodium carbonate solution in a mixture with toluene.
- the object of the invention is to provide a method for cross-coupling boronic acids or boric acids with olefinic or aromatic halogen compounds, which does not have the disadvantages of the previously used method and can be carried out on a large scale on an economical and risk-free basis. This object was achieved according to the invention by a process for the preparation of compounds of the general formula I.
- R 1 and R 2 each independently of one another are an unsubstituted or at least one halogen-substituted alkyl, alkoxy or alkylene radical having 1 to 15 carbon atoms, one or more CH 2 groups in these radicals each being independently of one another by —O -, -S-,
- R 2 also -H, -CN, -NCS, -NH 2 , -Cl, -F, -CF 3 , -OCF 3 , -OCF 2 H or
- Z 1 and Z 2 each independently of one another -CO-O-, -O-CO-,
- x 1 , x 2 , x 3 , x 4 , R 1 , R 2 , A 1 , Z 1 and n have the meaning given above and a chlorine, bromine or iodine compound general formula III wherein
- Y is Cl, Br or J and A 2 , Z 2 , R 2 , x 1 , x 2 , x 3 , x 4 and m have the meaning given above, in a solvent-water mixture in the presence of a transition metal catalyst and a water-soluble one Promoter implemented.
- Suitable as a promoter are all compounds that formally form a mixed boronic or boric anhydride of the general formula ⁇
- Y is a central atom or a molecular unit that is able to create bonds to both boronic acid and palladium via oxygen.
- the central atom can be - boron, for example as H 3 BO 3 or polyboric acid,
- Silicon for example as Na 2 SiO 3 ,
- Sulfur for example as Na 2 SO 4 , Na 2 SO 3 , Na 2 S 2 O 3 , phosphorus, for example as H 3 PO 4 and H 3 PO 3 and their
- Carbon for example as mono- or dicarboxylic acid, - an alkaline earth metal, titanium or aluminum, for example as a hydroxide or ester.
- Preferred additives are magnesium hydroxide, calcium hydroxide, sodium sulfate, sodium silicate and borates.
- Water-soluble borates such as borax and boron compounds that form borates in water such as NaBH 4 can be used. It is useful to have one
- buffer solution pH 8 Borate-hydrochloric acid buffer, for example "buffer solution pH 8", manufactured by E. MERCK, Darmstadt.
- the buffer solution can, for example, be placed in the reaction vessel and metered in during the reaction while maintaining the above-mentioned pH.
- the cross coupling is carried out at a pH of 5 to 14, preferably in the range from 5.5 to 9.
- Transition metal catalysts for example tetrakis (triphenylphosphine) palladium (II) chloride, 1,1'-bis (diphenylphosphino) -ferrocene-palladium (II) chloride or bis (tricyclohexylphosphine) palladium (II) chloride, the latter two optionally also as catalysts NaBH 4 pre-reduced, can be used.
- the reaction temperature is in the range from 20 ° C to 150 ° C. It is preferably set to a range from 60 ° C to 100 ° C.
- Suitable solvents are hydrocarbons, such as toluene and ethereal solvents, for example
- Tetrahydrofuran halogenated hydrocarbons and acidic solvents are unsuitable as solvents for the reaction. It is preferred to work in a solvent-water mixture. The tetrahydrofuran-water mixture is particularly preferred.
- boronic acids according to the general formula II can be used as boronic acids, the advantage of the process being particularly clear in the case of ortho-substituted boronic acids, since these are very easily proton-deboronized under the usual coupling conditions.
- vinyl boronic acids are also of the general formula
- the corresponding boric acids, organyl 2 -B-OH, and the corresponding boronic anhydrides can also be used.
- the halogen compounds of the general formula III can be used as halogen compounds.
- aliphatic phosphines are used as ligands, such as tricyclohexylphosphines.
- Suitable monodentate antimony compounds are
- Suitable bidentate ligands are
- R 1 is each independently straight-chain or
- R 2 straight-chain or branched C 1-6 alkyl, C 1 _ 6 alkoxy,
- the process according to the invention has the advantage that all synthesis steps can be carried out in a temperature range which can be mastered without technical difficulties.
- Lithiation of fluoroaromatics at -78 ° C with subsequent iodination at the same temperature can be saved by the previous method. Furthermore, the range of compounds that can be used is higher, since sterically hindered boronic acid compounds, such as the so-called
- Form fluoroboronic acids (2, 6-difluoroarylboronic acids) can be implemented. Compared to the previous process, there is no CO 2 development, which further improves the feasibility of the process on an industrial scale, especially with regard to safety.
- the synthesis sequence according to the invention achieves a time saving of up to 90%. While two days are required for the synthesis in the classic process, the reaction in the process according to the invention is completed in 3 to 4 hours. It is also advantageous that yields of up to 90% can be achieved by the process according to the invention and the unreacted boronic acid can be recovered from the reaction mixture by simple crystallization. The competitive reaction of proton deboronization is largely suppressed.
- pH 8 buffer 40 ml of pH 8 buffer (manufactured by E. MERCK, Darmstadt) were added and the mixture was heated to 50 ° C. The pH meter showed a pH of 9.
- Example 2 2.4 g of NaOH (0.06 mol) were placed in 75 ml of water in the reaction vessel and 1.75 g of Mg (OH) 2 (0.03 mol) were added as a promoter. Then 75 ml of toluene and 7.4 g of 4- (4-propylcyclohexyl) phenylboronic acid (0.03 mol) were added. After a stirring time of 5 min. 4.2 g (0.03 mol) of 4-chlorobenzonitrile and 0.18 g of PdCl 2 (2 mol%) and 0.34 g were added to the mixture
- Tricylohexylphosphin (4 mol%) added as a catalyst.
- the mixture was heated to boiling temperature, refluxed for 2 hours, cooled to room temperature, suction filtered through a filter, the filter was washed with toluene and water and the organic phase was separated off. After the aqueous phase had been extracted again with toluene, the organic phases were combined, washed twice with water, dried, filtered and the toluene was distilled off. 10.1 g of crude product containing 95.4% of 4- (4-propylcyclohexyl) biphenyl-4'-carbonitrile were obtained. The yield was more than 95%.
- Example 3 Example 3
- Example 2 treated further.
- the relatively low yield can be explained by the fact that a crude boronic acid mixture was used.
- Example 2 4- (4-propylcyclohexyl) phenylboronic acid and 4-chlorobenzonitrile were converted to 4- (4-propylcyclohexyl) biphenyl-4'-carbonitrile (designated B in Table 1).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93912904A EP0601156A1 (de) | 1992-06-19 | 1993-06-07 | Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungen |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4220082 | 1992-06-19 | ||
DE4220082A DE4220082C2 (de) | 1992-06-19 | 1992-06-19 | Verfahren zur Kreuzkopplung von Boronsäuren mit Halogenverbindungen |
EP93107956 | 1993-05-15 | ||
EP93107956 | 1993-05-15 | ||
PCT/EP1993/001432 WO1994000423A1 (de) | 1992-06-19 | 1993-06-07 | Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungen |
EP93912904A EP0601156A1 (de) | 1992-06-19 | 1993-06-07 | Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungen |
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EP0601156A1 true EP0601156A1 (de) | 1994-06-15 |
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EP93912904A Withdrawn EP0601156A1 (de) | 1992-06-19 | 1993-06-07 | Verfahren zur kreuzkopplung von boronsäuren mit halogenverbindungen |
Country Status (5)
Country | Link |
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EP (1) | EP0601156A1 (ja) |
JP (1) | JP3833698B2 (ja) |
KR (1) | KR100266113B1 (ja) |
DE (1) | DE4220082C2 (ja) |
WO (1) | WO1994000423A1 (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4414499A1 (de) * | 1994-04-26 | 1995-11-02 | Hoechst Ag | Verfahren zur Kreuzkupplung von aromatischen Borverbindungen mit aromatischen Halogenverbindungen oder Perfluoralkylsulfonaten |
DE4415049A1 (de) * | 1994-04-29 | 1995-11-02 | Hoechst Schering Agrevo Gmbh | Acylierte Aminophenylsulfonylharnstoffe, Verfahren zu deren Herstellung und Verwendung als Herbizide und Wachstumsregulatoren |
US5618934A (en) * | 1994-05-17 | 1997-04-08 | Merck & Co., Inc. | Boronic acid compound |
DE4423061C1 (de) * | 1994-07-01 | 1996-01-18 | Hoechst Ag | Verfahren zur Herstellung von Biphenylen mit Palladacyclen als Katalysatoren |
DE4426671A1 (de) * | 1994-07-28 | 1996-02-01 | Hoechst Ag | Verfahren zur Kreuzkupplung von aromatischen Borverbindungen mit aromatischen Halogenverbindungen oder Perfluoralkylsulfonaten |
DE19527118A1 (de) * | 1995-07-25 | 1997-01-30 | Hoechst Ag | Verfahren zur Durchführung von Kreuzkupplungsreaktionen |
GB9621222D0 (en) * | 1996-10-11 | 1996-11-27 | Zeneca Ltd | Process |
DE10211597A1 (de) | 2002-03-15 | 2003-10-02 | Merck Patent Gmbh | Verfahren zur Herstellung von Ringverbindungen |
JP5975081B2 (ja) * | 2013-09-30 | 2016-08-23 | ダイキン工業株式会社 | 含フッ素ビアリール化合物の製造方法 |
JP7231389B2 (ja) * | 2018-11-26 | 2023-03-01 | 帝人株式会社 | フルオレン骨格を有する化合物の製造方法および不純物の少ないフルオレン骨格を有する化合物 |
CN109704914A (zh) * | 2019-01-19 | 2019-05-03 | 山东理工大学 | 一种1,1-二氟乙基芳香化合物的简易合成新方法 |
CN111533649B (zh) * | 2020-06-01 | 2023-03-21 | 南京工业大学 | 一种酸类化合物的合成方法 |
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BR9007097A (pt) * | 1989-12-06 | 1992-02-18 | Merck Patent Gmbh | Compostos de 2,6-difluorbenzeno 1,4-dissubstituidos e meio cristalino liquido |
-
1992
- 1992-06-19 DE DE4220082A patent/DE4220082C2/de not_active Expired - Lifetime
-
1993
- 1993-06-07 WO PCT/EP1993/001432 patent/WO1994000423A1/de not_active Application Discontinuation
- 1993-06-07 JP JP50198094A patent/JP3833698B2/ja not_active Expired - Fee Related
- 1993-06-07 EP EP93912904A patent/EP0601156A1/de not_active Withdrawn
- 1993-06-07 KR KR1019940700482A patent/KR100266113B1/ko not_active IP Right Cessation
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Also Published As
Publication number | Publication date |
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JPH07502751A (ja) | 1995-03-23 |
JP3833698B2 (ja) | 2006-10-18 |
DE4220082A1 (de) | 1993-12-23 |
WO1994000423A1 (de) | 1994-01-06 |
KR100266113B1 (ko) | 2000-09-15 |
DE4220082C2 (de) | 1994-09-15 |
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