WO2012085170A2 - Process for making organoboron compounds, products obtainable thereby, and their use - Google Patents
Process for making organoboron compounds, products obtainable thereby, and their use Download PDFInfo
- Publication number
- WO2012085170A2 WO2012085170A2 PCT/EP2011/073716 EP2011073716W WO2012085170A2 WO 2012085170 A2 WO2012085170 A2 WO 2012085170A2 EP 2011073716 W EP2011073716 W EP 2011073716W WO 2012085170 A2 WO2012085170 A2 WO 2012085170A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- independently represents
- atom
- boron
- anion
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000008569 process Effects 0.000 title claims abstract description 14
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229910052796 boron Inorganic materials 0.000 claims abstract description 41
- 229910052751 metal Inorganic materials 0.000 claims abstract description 34
- 239000002184 metal Substances 0.000 claims abstract description 34
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 33
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 18
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 14
- 150000001768 cations Chemical group 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 10
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 9
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 4
- 125000002346 iodo group Chemical group I* 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 3
- 238000006880 cross-coupling reaction Methods 0.000 claims description 39
- 150000001450 anions Chemical class 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 23
- 125000001931 aliphatic group Chemical group 0.000 claims description 17
- 230000003647 oxidation Effects 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- PPWPWBNSKBDSPK-UHFFFAOYSA-N [B].[C] Chemical compound [B].[C] PPWPWBNSKBDSPK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000000962 organic group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 125000003172 aldehyde group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 45
- 239000000047 product Substances 0.000 abstract description 22
- 239000000376 reactant Substances 0.000 abstract description 13
- 125000000524 functional group Chemical group 0.000 abstract description 10
- 150000001299 aldehydes Chemical class 0.000 abstract description 6
- 239000003586 protic polar solvent Substances 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001298 alcohols Chemical class 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 239000000758 substrate Substances 0.000 description 31
- -1 ^-propyl Chemical group 0.000 description 26
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 20
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 125000004122 cyclic group Chemical group 0.000 description 16
- 239000002904 solvent Substances 0.000 description 13
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000011777 magnesium Substances 0.000 description 12
- 150000002739 metals Chemical class 0.000 description 12
- 229910002666 PdCl2 Inorganic materials 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- 229910052749 magnesium Inorganic materials 0.000 description 11
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- 239000012039 electrophile Substances 0.000 description 9
- 238000003780 insertion Methods 0.000 description 9
- 230000037431 insertion Effects 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 7
- QOGHRLGTXVMRLM-UHFFFAOYSA-N 4-bromo-1,2-dimethylbenzene Chemical group CC1=CC=C(Br)C=C1C QOGHRLGTXVMRLM-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000000129 anionic group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001649 bromium compounds Chemical class 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 150000002390 heteroarenes Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229940078552 o-xylene Drugs 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- FIIKVSVCOKUBEK-UHFFFAOYSA-N (4-chlorophenyl)-(3,4-dimethylphenyl)methanol Chemical compound C1=C(C)C(C)=CC=C1C(O)C1=CC=C(Cl)C=C1 FIIKVSVCOKUBEK-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 2
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000002879 Lewis base Substances 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000005524 benzylchlorides Chemical class 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- NVNNVKMNSDBHSA-UHFFFAOYSA-N diethyl 2-[(4-cyanophenyl)methyl]benzene-1,4-dicarboxylate Chemical compound CCOC(=O)C1=CC=C(C(=O)OCC)C(CC=2C=CC(=CC=2)C#N)=C1 NVNNVKMNSDBHSA-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 description 2
- UJLVPEHEEIFXQV-UHFFFAOYSA-N ethyl 4-(3,4-dimethylphenyl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C1=CC=C(C)C(C)=C1 UJLVPEHEEIFXQV-UHFFFAOYSA-N 0.000 description 2
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 150000007527 lewis bases Chemical class 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 150000001457 metallic cations Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CTXKJNCPTVBAAU-UHFFFAOYSA-N phenylmethoxyboronic acid Chemical class OB(O)OCC1=CC=CC=C1 CTXKJNCPTVBAAU-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000010414 supernatant solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 description 2
- 238000007514 turning Methods 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- 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
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- SRXJYTZCORKVNA-UHFFFAOYSA-N 1-bromoethenylbenzene Chemical compound BrC(=C)C1=CC=CC=C1 SRXJYTZCORKVNA-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- BNXZHVUCNYMNOS-UHFFFAOYSA-N 1-butylpyrrolidin-2-one Chemical compound CCCCN1CCCC1=O BNXZHVUCNYMNOS-UHFFFAOYSA-N 0.000 description 1
- UQQAFBGSIJZWIP-UHFFFAOYSA-N 2-bromo-6-ethoxy-3-ethoxycarbonylbenzoic acid Chemical compound CCOC(=O)c1ccc(OCC)c(C(O)=O)c1Br UQQAFBGSIJZWIP-UHFFFAOYSA-N 0.000 description 1
- OHWSWGXNZDSHLM-UHFFFAOYSA-N 2-chloro-3-iodopyridine Chemical compound ClC1=NC=CC=C1I OHWSWGXNZDSHLM-UHFFFAOYSA-N 0.000 description 1
- JHBIKYYSLFCTCS-UHFFFAOYSA-N 2-chloro-3-thiophen-3-ylpyridine Chemical compound ClC1=NC=CC=C1C1=CSC=C1 JHBIKYYSLFCTCS-UHFFFAOYSA-N 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- LJXMGBDKJSRCNR-UHFFFAOYSA-N 4-amino-3-(4-hydroxyphenyl)benzonitrile Chemical compound NC1=CC=C(C#N)C=C1C1=CC=C(O)C=C1 LJXMGBDKJSRCNR-UHFFFAOYSA-N 0.000 description 1
- UOWVTQFTEAYDLM-UHFFFAOYSA-N 4-amino-3-iodobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1I UOWVTQFTEAYDLM-UHFFFAOYSA-N 0.000 description 1
- BLNFMQMOXUNBJU-UHFFFAOYSA-N 5-bromo-5,6-bis(trifluoromethyl)cyclohexa-1,3-diene Chemical compound BrC1(C(C=CC=C1)C(F)(F)F)C(F)(F)F BLNFMQMOXUNBJU-UHFFFAOYSA-N 0.000 description 1
- LGFDQZCUDVWAIQ-UHFFFAOYSA-N CCOC(c(cc1)ccc1-c(cc1)ccc1OC)=O Chemical compound CCOC(c(cc1)ccc1-c(cc1)ccc1OC)=O LGFDQZCUDVWAIQ-UHFFFAOYSA-N 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N COc(cc1)ccc1Br Chemical compound COc(cc1)ccc1Br QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- HTIRHQRTDBPHNZ-UHFFFAOYSA-N Dibutyl sulfide Chemical compound CCCCSCCCC HTIRHQRTDBPHNZ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical group 0.000 description 1
- 150000003868 ammonium compounds Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 229950007134 bromofos Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 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 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 239000007862 dimeric product Substances 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- AIVDOEANRQJHDP-UHFFFAOYSA-N ethyl 4-(1-phenylethenyl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C(=C)C1=CC=CC=C1 AIVDOEANRQJHDP-UHFFFAOYSA-N 0.000 description 1
- XZIAFENWXIQIKR-UHFFFAOYSA-N ethyl 4-bromobenzoate Chemical compound CCOC(=O)C1=CC=C(Br)C=C1 XZIAFENWXIQIKR-UHFFFAOYSA-N 0.000 description 1
- KAWVJHZGUMSPEI-UHFFFAOYSA-N ethyl 4-iodobenzoate 2-(4-iodophenyl)propanoic acid Chemical compound IC1=CC=C(C=C1)C(C(=O)O)C.IC1=CC=C(C=C1)C(=O)OCC KAWVJHZGUMSPEI-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 238000009815 homocoupling reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000010892 non-toxic waste Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000005000 thioaryl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- IJJNTMLAAKKCML-UHFFFAOYSA-N tribenzyl borate Chemical compound C=1C=CC=CC=1COB(OCC=1C=CC=CC=1)OCC1=CC=CC=C1 IJJNTMLAAKKCML-UHFFFAOYSA-N 0.000 description 1
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- JQKHNBQZGUKYPX-UHFFFAOYSA-N tris(2,4,6-trimethoxyphenyl)phosphane Chemical compound COC1=CC(OC)=CC(OC)=C1P(C=1C(=CC(OC)=CC=1OC)OC)C1=C(OC)C=C(OC)C=C1OC JQKHNBQZGUKYPX-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
-
- 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
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
- C07D295/30—Nitrogen atoms non-acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D343/00—Heterocyclic compounds containing rings having sulfur and selenium or sulfur and tellurium atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07F5/04—Esters of boric acids
-
- 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
-
- 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
Definitions
- the present invention relates to the field of metal insertion in the presence of boron-based compounds to make compounds useful in Suzuki-type cross-coupling reactions.
- Organometallic reagents are of increasing importance in organic chemistry, especially as key intermediates for the synthesis of biologically active compounds as well as natural products.
- transition metal catalyzed cross-couplings such as the Negishi, Stille, Heck and Suzuki -Miy aura types have become widely used synthetic tools for the concise construction of polyfunctional aromatics and
- organoborates as organometallic intermediates.
- the organoboron compounds such as organotrifluoroborates generally show a high tolerance towards functional groups and thermal stability.
- the Suzuki type reactions can even be conducted in protic or aqueous solvents producing merely non-toxic waste which makes them frequently used reactions in academic institutions and industry.
- organoboron intermediates have had major drawbacks. Besides commonly used multi-step reactions via highly reactive organometallics, the direct syntheses of organoboron compounds has been difficult, has had a low atom-economy or a low yield due to side-reactions and/or byproducts, or has required expensive transition-metal catalysis or expensive catalytic boranes, such as pinacolboranes and catecholboranes.
- the known synthetic routes and/or the use of borohydrides have also had a low tolerance towards sensitive functional groups.
- One aspect of the invention is a process for making boron-containing organic compounds (also referred to herein as "organoboron compounds”) comprising reacting at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent with at least one boron-containing reagent represented by the chemical formula (IA) or (IB):
- each Y independently represents an oxygen atom, a sulfur atom, or - R'-
- each R 1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms
- Cat is a cation or mixture of cations
- n is a positive number in the range from 1 to 3.
- Another aspect of the invention is a mixture comprising components (A) and
- each Y independently represents an oxygen atom, a sulfur atom, or - R'-
- each R 1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms
- each R 2 independently represents an organic moiety bonded to the boron atom of the anion or compound via a carbon - boron covalent bond
- each "a” and "b” represents an integer in the range from 0 to 2
- each sum of "a” + "b” per boron atom is in the range from 1 to 2, and
- the molar ratio of component (B) to component (A) is at least 1 : 100.
- a further aspect of the invention is anions comprising at least one moiety represented by the formula (IIA):
- each Y independently represents an oxygen atom, a sulfur atom or -NR'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
- each R 1 independently represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms, and
- each R 2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b” represents an integer in the range from 0 to 2, and
- each sum of "a” + “b” per boron atom is in the range from 1 to 2.
- compounds comprising at least one moiety represented by formula (IV) and (IIB):
- each Y independently represents an oxygen atom, a sulfur atom, or - R'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
- each R 1 independently represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
- each R 2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising an alkynyl group, a benzyl group or one or more hetero atoms,
- each "a” and "b” represents zero or 1
- each sum of "a” + "b” per boron atom is equal to 1 or 2, preferably 1.
- Another aspect of this invention is methods for cross-coupling organic compounds comprising reacting the above-described mixture, anion and/or compound with at least one organic compound having at least one CI, Br, I, nucleophilic leaving group or aldehyde substituent.
- the organoboron products of the invention are useful for conducting coupling reactions and reactions with aldehydes. Due to their selectivity, such reactions may be conducted in protic solvents, such as water and alcohols, and sensitive functional groups in the reactants are maintained in the final product.
- protic solvents such as water and alcohols
- sensitive functional groups in the reactants are maintained in the final product.
- the organoboron products are stable, so that they maintain their activity during storage.
- Fig. 1 shows percent cross-coupling conversion for various catalysts based on the illustrated cross-coupling reaction according to the invention.
- protic or “protic hydrogen atom(s)” refers to acidic hydrogen atom substituents (i.e., hydrogen atoms the protons of which may be removed through contact with a Lewis base). In general, hydrogen atoms not attached to carbon atoms may be considered protic. Examples of protic hydrogen atoms include the hydrogen atoms of carboxylic acids, aldehydes, phenols, alcohols, and amines.
- standard oxidation potential refers to the oxidation potential measured at pH 14 under standard temperature and concentration conditions.
- the oxidation potential is, by definition, the exact opposite of the standard reduction potential reported in the literature (e.g., a reduction potential of - 1.0 V equals an oxidation potential of +1.0 V).
- Examples of the reduction potentials for metals and metal complexes may be found in Annex VI, page 1843, of Hollemann-Wiberg, LEHRBUCH DER ANORGANISCHEN CHEMIE, 101 ST edition (Walter de Gruyter, 1995).
- hetero atoms refers preferably to the atoms N, O, S, P, B, Si, and Se. More preferred hetero atoms are N, O, S, and P.
- Boron-containing reagents of formulae (IA) and (IB) are reacted with organic compounds having CI, Br, I, and/or nucleophilic leaving groups to make boron- containing compounds.
- the organic moieties R 1 and R' of formulae (IA) and (IB) may be selected from a wide range of moieties having at least 1 , preferably at least 2, more preferably at least 3, and even more preferably at least 4 up to 15, more preferably up to 10, and even more preferably up to 8, carbon atoms and, optionally, one or more hetero atoms.
- Preferred moieties may be selected from saturated or unsaturated, straight or branched, aliphatic groups, cyclic groups or combinations of the aforementioned aliphatic and cyclic groups.
- the cyclic groups may be monocyclic or polycyclic, saturated or unsaturated, carbocyclic or heterocyclic ring structures.
- the polycyclic ring structures may be fused ring structures, bridged ring structures and rings sharing one atom in common preferably comprising up to 3, more preferably up to 2, rings.
- the aliphatic and/or cyclic moiety may have one or more substituents.
- hetero atoms may be present as chain and/or ring member and/or
- the hetero atoms may, for example, form ethers, ketones, amides, amines, nitro, cyano, esters, sulfonyl, etc., which are preferably protected if they would otherwise contain an acidic hydrogen atom, CI, Br, I or nucleophilic leaving group. Some or all hydrogen atoms may be replaced by fluorine atoms.
- the organic moiety preferably does not contain protic (i.e., acidic) hydrogen atoms and preferably does not have CI, Br, I, or nucleophilic leaving group
- the organic moiety may be saturated or unsaturated, but is preferably saturated.
- R 1 groups examples include ethyl, ⁇ -propyl, isopropyl, «-butyl, sec-butyl, t-butyl, «-pentyl, «-hexyl, «-heptyl, «-octyl, «-nonyl, «-decyl, and n- dodecyl and the foregoing substituted with one or more substituents selected from the group methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl, and t-butyl.
- the Cat of formula IA is any cation that does not negatively interfere with, or detract from, the desired reactions and reaction products.
- Cat may be selected from alkali metal cations such as Li + , Na + , and K + , alkaline earth metal cations such as Mg 2+ and Ca 2+ , and quaternary amines such as tetralkyl ammonium compounds wherein the alkyl groups have 1 to 4, preferably 1-2, carbon atoms, such as N( «-Bu) 4 + and mixtures thereof.
- n in Formulae (IB) corresponds to the valence, or charge, of the cation(s).
- salt of formula (IB) contains a mixture of cations having different valences or charges
- n may have a fractional value representing the molar average charge of the cation mixture.
- the metals and metal complexes used in the process according to this invention may be any metal having a standard oxidation potential greater than the oxidation potential of the boron-containing reagent.
- the metals and metal complexes preferably have a positive standard oxidation potential at pH 14, more preferably a standard oxidation potential at pH 14 not less than 0.1 V, more preferably not less than 0.4 V, even more preferably not less than 0.7 V, yet more preferably not less than 1 V, even more preferably not less than 1.5 V, and still more preferably not less than 2 V.
- the metals are preferably in the zero (i.e., elemental) oxidation state when it is brought into contact with the other reactants.
- Preferred metals include Mg, Al, Ca, Zn, K, Li, and Na.
- the metals and metal complexes may be brought into contact with the other reactants in the form of solid metal turnings, shavings or nanoparticles.
- the metal complexes are preferably complexes of metals with a ligand.
- the ligand is an electron donor (i.e., Lewis base) ligand capable of donating a pair of electrons to a metal ion capable of accepting the electrons as a Lewis acid to form a coordination bond.
- suitable ligands include N(R') 3 , 0(R') 2 , OOC-R', P(0)(R') 3 , P(R' )3, and multidentate ligands having two or more of the foregoing ligands, preferably bonded to the same or adjacent carbon atoms of an organic compound molecule, wherein each R' independently has the same meaning, including preferred meanings, as defined above.
- Suitable ligands include PPh 3 , NEt 3 , imidazole, pyridine, acetate, and ethers.
- Multidentate ligands based on one or more of the aforementioned ligands are preferred.
- Suitable preferred metals include transition elements, such as Co, Cu, Fe, Cr, Mn, Mo, Os, Re and Ru, which have an oxidation state of at least +1.
- the metal and/or metal complex is preferably introduced into the reaction mixture when the other reactants are already present in admixture with each other, preferably in a solvent.
- An amount of metal and/or metal complex is introduced which is preferably sufficient to drive the reaction to completion. This can generally be assured by providing an excess amount of metal and/or metal complex, so that solid metal and/or metal complex remains in the reaction mixture when no further reaction activity is observed.
- the substrate for the reaction is at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent.
- Each nucleophilic leaving group is preferably selected from the group consisting
- R A , R c , R D , R E , and R F each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group preferably has B G
- Preferred hydrocarbyl groups include methyl, branched-chain and straight-chain aliphatic hydrocarbons such as ethyl, propyl, isopropyl, «-butyl, sec-butyl and t-butyl, and aromatic hydrocarbons such as phenyl and benzyl.
- Preferred fluorocarbyl groups include -(CF 2 ) m CF 3 , wherein "m" represents an integer in the range from zero to 4 and fluorinated aryl groups, such as fluorinated benzyl groups.
- Preferred nucleophilic leaving groups include triflates (-OS(0) 2 CF 3 ); mesylates (-OS(0) 2 CH 3 ); nonaflates (-OS(0) 2 (CF 2 ) 3 CF 3 ); tosylates (-OS(0) 2 C 6 H 5 CH 3 );
- diazonium salts such as ArN 2 BF 4 , wherein Ar represents an aryl group such as phenyl, benzyl, tolyl, xylyl, or naphthyl; acetate; pivalate; thiomethyl; and thioaryl, such as thiobenzyl.
- Preferred organic compounds may be represented by formula (V):
- R 5 represents an organic residue comprising one or more carbon atoms and, optionally, one or more hetero atoms
- L represents CI, Br, I, or a nucleophilic leaving group, such as the preferred
- p represents an integer in the range from 1 up to 10, preferably up to 4, more preferably up to 2, and even more preferably up to 1.
- the organic residue, R 5 preferably does not comprise protonated hetero atoms such as, for example, OH, H, or SH and preferably comprises one or more cyclic groups and/or one or more aliphatic groups.
- the cyclic groups may comprise carbocyclic groups, such as cycloalkyl groups and aryl groups, and heterocyclic groups, such as heteroaryl groups and partially or fully saturated heterocyclic compounds.
- Preferred cyclic groups have at least 4, more preferably at least 5, and even more preferably at least 6, up to 20, more preferably up to 15, and even more preferably up to 10, carbon atoms and optionally from 1 preferably up to a number of hetero atoms equal to the number of carbon atoms in the cyclic group.
- the heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S.
- the cyclic group may comprise a monocyclic or polycyclic ring system.
- the polycyclic ring system may comprise fused ring systems, bridged ring systems and rings having one atom in common.
- Preferred carbocyclic groups are aryl cycloalkyl groups,and cycloalkenyl groups, such as phenyl groups, napththalene rings, cyclohexyl groups, cyclohexenyl groups, cyclopentyl groups, cyclopentenyl groups, etc.
- heterocyclic groups include heteroaryl groups having 5, 6, or 7 ring members and 1, 2, or 3 hetero atoms.
- heterocyclic groups containing one or more nitrogen atoms as ring members include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, isoxazolyl, furazanyl, pyridinyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, morpholinyl or morpholino, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalin
- oxygen-containing heterocyclic groups other than those previously mentioned among nitrogen atom-containing heterocyclic groups include furyl, pyranyl, isobenzofuranyl, chromenyl, chromanyl, iaochromanyl, and xanthenyl.
- the aliphatic group preferably comprises at least 2, more preferably at least 3, and even more preferably at least 4, up to 20, more preferably up to 12, and even more preferably up to 8, and even more preferably up to 6, carbon atoms.
- the aliphatic group may be straight-chained or branched, may comprise one or more heteroatoms representing up to half, more preferably up to one-fourth, the total number of atoms in the aliphatic group, and may comprise one or more unsaturated bonds.
- the heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S.
- the unsaturated bonds are preferably double bonds and triple bonds.
- Preferred aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups.
- the aliphatic groups are preferably saturated (i.e., do not contain unsaturated bonds).
- the substituents when present, are preferably selected from among the aforementioned preferred R 1 cyclic and aliphatic groups bonded directly to the aforementioned cyclic or aliphatic groups or bonded indirectly to the same via a Y group as defined above.
- Preferred substituents also include fluorine atoms and nonprotic functional groups.
- Preferred functional group substituents are nitrile, nitro, ester, amide, protected alcohol, protected amine and protected amide.
- the ester group is preferably represented by the formula -C(0)OR 3 , wherein R 3 is an organic moiety, which may be selected from each and every option presented for R 1 of Formula (I) above.
- Protected alcohol, protected amine and protected amide are alcohol, amine and amide groups in which each proton bonded to an oxygen atom or nitrogen atom has been replaced with a group that is less reactive than the proton and yet capable of being removed to permit reactions to take place on the respective groups.
- Suitable protecting groups for those functionalities are well known in the state of the art. A description of suitable protective groups is provided, for example, in "Protective groups in organic synthesis" T. W. Greene, P. G. M: Wuts, Wiley.
- An example is TIPS to protect alcoholic and phenolic OH groups. Reaction conditions
- the syntheses of organoboron compounds is preferably conducted at a temperature in the range from -30°C, more preferably from -10°C, up to, but not including, the decomposition temperature of the reactant having the lowest
- the reaction may preferably be conducted at temperatures in the range from 10°C, more preferably from 20°C up to 50°C, more preferably up to 30°C, such as at ambient (e.g., room) temperature.
- the reaction is generally conducted under the exclusion of oxygen, or air, in an nonprotic, preferably inert, solvent under an inert atmosphere, such as argon gas, until conversion is complete.
- Suitable inert nonprotic solvents include, but are not limited to, cyclic, linear or branched mono- or polyethers such as THF, Me-THF, dibutyl ether, diethylether, tert-butylmethylether, dimethoxyalkylether, and dimethoxyalkanes; thioethers such as dimethyl sulfide and dibutyl sulfide; tertiary amines such as triethylamine, and ethyldiisopropylamine; phosphines; aromatic hydrocarbons, such as benzene, toluene and xylene; heteroaromatic hydrocarbons such as pyridine, N- methyl -2-pyrrolidone (NMP), N-eth
- urea derivatives such as ⁇ , ⁇ '-dimethylpropylene urea (DMPU) and ⁇ , ⁇ , ⁇ ', ⁇ '-tetram ethyl urea; acetonitrile; and CS 2 either individually or two or more in combination.
- Cyclic ethers such as THF and Me-THF, are preferred.
- This reaction is preferably carried out in the substantial absence of protic solvents, such as water. Unless stated otherwise, the solvent has been dried to minimize the presence of protic solvents such as water.
- the reaction vessel, reactants and solvent are preferably dried or distilled before use to ensure that water is not present during the reaction.
- Synthesis of the organoboron compounds is preferably conducted in the presence of LiX, wherein X represents halide selected from CI, Br, and I. X is preferably CI. LiX has an accelerating effect on the synthesis of the organoboron compounds.
- the reaction rate is generally sufficient without a further catalyst, so that in a preferred embodiment the reaction is carried out in the absence of a transition metal catalyst.
- the reaction is preferably carried out in a one pot procedure.
- the reaction is preferably carried out by contacting a solution containing the organic compound substrate, at least one boron reagent and, preferably, LiX with the metal to generate the desired organoboron compound(s) in situ (i.e., without conducting transmetallation of the organic compound substrate in a separate step prior to reacting the metalated organic compound with a boron-containing compound).
- the process according to the invention produces organoboron compounds wherein the organic substrate molecules form bonds between the carbon atoms to which CI, Br, I, or an nucleophilic leaving group were attached and the boron atoms of the boron reagent to form various neutral or anionic species depending on the ratio of equivalents of the CI, Br, I, and nucleophilic leaving groups to boron atoms present in the reaction mixture and the nature of the solvent used to conduct the reaction.
- the ratio of equivalents influences the degree to which the organic compound substrate is substituted on the boron-containing reagents. Increasing the ratio of organic compound substrate to boron atoms increases the molar average number of organic compound substrate molecules bonded to the boron atoms of the boron- containing reagents. When the ratio of equivalents is greater than 1 : 1, a mixture of organoboron compounds may be produced having various degrees of organic compound substrate substitution.
- the organoboron product When the organoboron product is neutral, the organoboron product may comprise a mixture of one or more components comprising the following moieties:
- each "a” and “b” represents an integer in the range from 0 to 2 and each sum of "a” + “b” per boron atom is 1 or 2.
- the neutral compounds may comprise moieties represented by formula (IV) and (IIB):
- each Y and R 1 have the same meaning as defined in formulae (IA) and (IB) above.
- Each R 1 independently preferably represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
- each R 2 independently represents an organic moiety comprising an alkynyl group, a benzyl group or one or more hetero atoms, wherein the organic group is bonded to the boron atom of the moiety represented by formula (IIA) or (IIB) via a carbon - boron covalent bond, each "a" and "b" represents zero or 1, and
- each sum of "a” + “b” per boron atom is equal to 1.
- Conducting the reaction in nonprotic polar solvents tends to generate anionic organoboron species charge-balanced by cationic species generated in situ. This is in contrast to conducting the reaction in nonpolar solvents such as toluene, which tends to generate a greater proportion of neutral species.
- nonpolar solvents such as toluene
- the generation of anionic organoboron species in nonprotic polar solvents, such as THF is preferred.
- the organoboron product When the organoboron product is anionic and the ratio of equivalents of organic compound substrate to boron-containing reagent is greater than 1 : 1, the organoboron product may comprise a mixture of one or more of anionic components comprising the following moieties:
- each Y, R 1 , and R 2 have the same meaning as defined above,
- each "a” and "b” represents an integer in the range from 0 to 2
- each sum of "a” + "b” per boron atom is in the range from 1 to 2, and
- the product of the reaction is a mixture comprising components (A) and (B):
- each Y and R 1 have the same meanings as defined above in formulae (IA) and (IB), each R 2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond, each "a" and "b” represents an integer in the range from 0 to 2,
- each sum of "a” + "b” per boron atom is in the range from 1 to 2, and
- the molar ratio of component (B) to component (A) is at least 1 : 100, preferably at least 1 :50, and more preferably at least 1 :20.
- the preferred anions comprise moieties represented by the formula (IIA) and/or (IIB):
- each Y and R 1 has the same meaning as in formulae (IA) and (IB) above.
- R 1 preferably represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
- each R 2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b” represents an integer in the range from 0 to 2,
- each sum of "a” + "b” per boron atom is in the range from 1 to 2, and
- the sum of "a” and “b” per formula (IIB) molecule is at least 4, preferably at least 5.
- the anions are accompanied by a charge-balancing amount of cations.
- the cations comprise the metallic cations formed by oxidizing the metal during the reaction, cations introduced via salts of formula (IB), when present, and Li + introduced via LiX.
- the organoboron-containing mixtures, salts and compounds may be isolated and, if necessary, dried or dispersed or dissolved in a wide range of solvents. Once formed, the products are stable not only in the solvents used to synthesize the product, but also in a variety of protic solvents as well, such as water and various alcohols, for example.
- the above-described organoboron mixtures, anions and compounds are useful for conducting coupling reactions with electrophiles, such as the Suzuki-type cross- coupling reactions and, in particular, the Suzuki-Miy aura-type cross-coupling reactions.
- the electrophiles are organic compounds having at least one CI, Br, I, or nucleophilic leaving group.
- the nucleophilic atoms and groups react with the organoboron anions and compounds disclosed herein to make organic compounds that are larger and/or more complex than the organic compound substrate that was used to make the organboron anions and compounds.
- the electrophile may be reacted with the above-described organoboron compounds in the presence of a cross-coupling catalyst to couple the electrophile residue with the organo portion of the organoboron compound.
- the organoboron products may be used to conduct cross- coupling with organic compounds that have, in addition to the electrophilic atom(s) or group(s), functional groups having sensitive functional groups, such as -OH groups, carboxylic acid groups, and the like, without requiring replacement of the protic hydrogen atoms with protective groups prior to conducting the reaction.
- the choice of electrophiles is therefore much broader than the choice of organic compound substrates for synthesizing the organoboron compounds of the invention.
- Examples of sensitive functional groups on the electrophile tolerated during cross-coupling include, for example, nitrile groups, -OH groups, acid groups, ester groups, amide groups, aldehyde groups, keto groups and cyano groups.
- Cross-coupling is conducted with a catalyst and a base.
- the cross-coupling catalyst and base is preferably selected from the types used in state of the art Suzuki- type, or in particular the Suzuki-Miyaura-type, cross-coupling reactions.
- Appropriate catalysts and bases are well-known.
- Preferred catalysts comprise one or more palladium or nickel atoms.
- Examples of preferred catalysts include PdCl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2> PdCl 2 , which surprisingly may be used without stabilizing ligands, and NiBr 2 (PPh 3 ) 4 .
- An example of a base is a basic alkali metal salt, such as an alkali metal phosphate.
- An example is potassium phosphate.
- reaction conditions for conducting cross-coupling are the same as, or analogous to, the preferred conditions for synthesizing the organoboron mixtures, anions, and compounds according to the invention. Further details on how to conduct such cross-coupling reactions are provided in S. R. Chemler, D. Trauner, S. J.
- aldehyde groups react with the organoboron via a secondary addition reaction to link the organo portion of the organoboron with the organic compound bearing the aldehyde via a secondary alcohol.
- the organic compound to be added to the organo portion of the organoboron compound does not need to undergo cross-coupling and therefore does not require an electrophilic atom or group substituent, nor cross- coupling catalyst or base.
- Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent) with various borates (0.33 equivalent) and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 20 minutes at 25°C in dry THF as the solvent.
- the reaction produced a reaction mixture containing reaction products in which the boron atom of the former borate reactant has from 1 to 4 o-xylene substituents bonded at the o-xylene 4-position and from 1 to 3 of the alkoxy or aceto groups of the organoborate was replaced by o-xylene at the o-xylene 4-position.
- the boron product was substantially anionic (i.e., boron with 4 subsituents) with Mg 2+ generated via oxidation of the magnesium turnings as the primary cationic counter-ion.
- the most prevalent organoborate anion had two o-xylene groups, wherein one of the o-xylene groups replaced an alkoxy or acetoxy substituent formerly on the borate reactant.
- the conversion rate is also affected by the ratio of equivalents between organohalide substrate and the borate reactant.
- Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent, referred to below as the "substrate") with tributylb orate (referred to below as the “borate") and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 30 minutes at 25°C in dry THF as the solvent.
- the respective substrate to borate equivalent ratios and the percent conversions of the 4-bromo-o-xylene to the organoborate are shown in Table 2.
- the metal used to drive the reaction may be selected from any one of the metals listed in Table 3. Of those metals, the highest reaction rates and yields for this reaction are obtained with Li and Al followed by Ca and Na. Yields greater than 80%> are attained for K and Zn in 12 hours or less.
- Tributylb orate (0.5 equivalent) and Mg are reacted with 4-bromoxylene (1 equivalent) in the presence of LiCl in dry THF at 25°C for 30 minutes to make the xylene- substituted boron compound with 90% yield.
- the reaction mixture is then reacted with ethyl 4-iodophenylcarboxylate (4-iodophenylpropionate) in a 3 : 1 mixture of THF to methanol in the presence of 4 mol% catalyst selected according to Fig. 1 and 1 equivalent potassium phosphate for 12 hours at 65°C to form the title compound 6a
- the organoborates of the invention can be cross-coupled to produce the desired product in high yield using a wide variety of palladium and nickel catalysts, including catalysts in which the metal atom is not stabilized by ligands such as dppp, dppe, dba, TTMPP, and acac.
- Example 6 To demonstrate the suitability of the organoborates for cross-coupling functionalized organic compounds, functionalized aryl bromides 4a-e are reacted with magnesium turnings (1.6 equiv) in the presence of B(OBu) 3 (0.5 equiv) and LiCl (1.1 equiv) in a 1 : 1 mixture of THF and ethanol providing the corresponding arylborates 5a-e in ca. 90% yield.
- Functionalized heteroaryl bromides and benzyl chlorides 4g-j may also be reacted with magnesium in the presence of B(OBu) 3 to furnish, after subsequent cross-coupling with substituted aryl iodides or bromides 7g and 7j-m in a 1 : 1 mixture of THF and ethanol or DMF at 65°C according to conditions [a] to [d] described in the footnotes below, polyfunctional aromatics 61-p (Table 5, entries 1-5).
- the obtained product is water-stable, hence convenient for subsequent reactions.
- Functionalized primary and secondary alkylborates as well as allylborates may also be prepared by direct magnesium insertion as shown in Table 6 below.
- Lithium chloride is then added to the above room temperature solution and the solution is contacted with magnesium metal turnings for 2 hours at 25°C to form the arylborates.
- the arylborates are then combined with 1 equivalent of 4-cyano-2-iodo- aniline (electrophile) per 0.5 equivalent of the arylborate, 2 equivalent cesium carbonate (base) per equivalent of electrophile and enough methanol to provide a mixture with THF in a 1 : 1 ratio and the components of this mixture are reacted in the presence of 4 mol% Pd(PPh 3 ) 4 (catalyst) for 1 hour at 65°C.
- the substrate l-bromo-fos(trifluoromethyl)benzene 4a is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4a in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4a at 65°C for 1 h to make the /s(trifluoromethyl)phenylborate 5a in ca. 90% yield.
- the arylborate 5a is then subjected to Pd-catalyzed cross-coupling with ethyl 4- iodobenzoate (7a); together with 2 equivalent cesium carbonate (base) per equivalent of 7a in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% Pd(PPh 3 ) 4 (catalyst) at 65 °C for 12 h to produce the title polyfunctional arene 15a in 68% yield.
- the substrate ethyl 2-bromo-4-ethoxycarboxybenzoate 4k is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4k in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4k at 65°C for 7 h to make the 2,5-di(ethoxycarboxy)phenylborate 5k in ca. 90% yield.
- the arylborate 5k is then subjected to Pd-catalyzed cross-coupling with 4- bromobenzonitrile (7j); together with 2 equivalent cesium carbonate (base) per equivalent of 7j in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% PdCl 2 (dppf) (catalyst) and DMF at 65 °C for 12 h to produce the title polyfunctional arene 15b in 73% yield.
- the aldehyde addition reaction proceeds without the use of catalysts or promoters.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
A process for making organoboron compounds is disclosed in which at least one organic compound having at least one Cl, Br, or I atom or at least one nucleophilic leaving group substituent is reacted with at least one boron-containing reagent represented by the chemical formula (IA) or (IB): B(YR1)3 (IA) [Cat]n+[B(YR1)4
-]n (IB) in the presence of at least one oxidizable metal or oxidizable metal complex, wherein each Y independently represents an oxygen atom, a sulfur atom, or NR-, each R1 and each R independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms, Cat is a cation or mixture of cations, and n is a positive number in the range from 1 to 3. The organoboron products obtained by this process are useful for conducting coupling reactions and reactions with aldehydes. Due to their selectivity, such reactions may be conducted in protic solvents, such as water and alcohols, and sensitive functional groups in the reactants are maintained in the final product. The organoboron products are stable, so that they maintain their activity during storage.
Description
PROCESS FOR MAKING ORGANOBORON COMPOUNDS,
PRODUCTS OBTAINABLE THEREBY, AND THEIR USE
Field of the Invention
The present invention relates to the field of metal insertion in the presence of boron-based compounds to make compounds useful in Suzuki-type cross-coupling reactions.
Background of the Invention
Organometallic reagents are of increasing importance in organic chemistry, especially as key intermediates for the synthesis of biologically active compounds as well as natural products. In particular, transition metal catalyzed cross-couplings such as the Negishi, Stille, Heck and Suzuki -Miy aura types have become widely used synthetic tools for the concise construction of polyfunctional aromatics and
heteroaromatics.
In particular, the Suzuki -Miy aura cross-coupling reactions are highly practical and extensively used for straightforward C-C-bond formation by applying
organoborates as organometallic intermediates. The organoboron compounds such as organotrifluoroborates generally show a high tolerance towards functional groups and thermal stability. Moreover, the Suzuki type reactions can even be conducted in protic or aqueous solvents producing merely non-toxic waste which makes them frequently used reactions in academic institutions and industry.
However, the preparation of these organoboron intermediates has had major drawbacks. Besides commonly used multi-step reactions via highly reactive organometallics, the direct syntheses of organoboron compounds has been difficult, has had a low atom-economy or a low yield due to side-reactions and/or byproducts, or has required expensive transition-metal catalysis or expensive catalytic boranes, such as pinacolboranes and catecholboranes. The known synthetic routes and/or the use of borohydrides have also had a low tolerance towards sensitive functional groups.
Thus, there continues to be a need for a direct, facile and inexpensive route for making polyfunctional and heterocyclic organoborates having a greater tolerance for functional groups which can subsequently be used in cross-coupling reactions.
The present invention addresses this and other problems as further described below.
Summary of the Invention
One aspect of the invention is a process for making boron-containing organic compounds (also referred to herein as "organoboron compounds") comprising reacting at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent with at least one boron-containing reagent represented by the chemical formula (IA) or (IB):
B(YR1)3 (IA)
[Cat]n+[B(YR1)4 "]„ (IB)
in the presence of at least one oxidizable metal or oxidizable metal complex, wherein
each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
Cat is a cation or mixture of cations, and
n is a positive number in the range from 1 to 3.
Another aspect of the invention is a mixture comprising components (A) and
(B):
(A) at least one anion comprising at least one moiety represented by the formula (IIA)
R2 2B(YR1)2 (IIA) and/or a compound or anion comprising at least one moiety represented by formula (ΠΒ)
(B(R2)a(YR1)bY)3 (ΠΒ) and
(B) at least one anion comprising at least one moiety represented by the formula (III)
R2 4B (III),
wherein
each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety bonded to the boron atom of the anion or compound via a carbon - boron covalent bond,
each "a" and "b" represents an integer in the range from 0 to 2,
each sum of "a" + "b" per boron atom is in the range from 1 to 2, and
the molar ratio of component (B) to component (A) is at least 1 : 100.
A further aspect of the invention is anions comprising at least one moiety represented by the formula (IIA):
R2 2B(YR1)2 (IIA) and/or
compounds and anions comprising at least one moiety represented by formula (IIB)
(B(R2)a(YR1)bY)3 (IIB),
wherein
each Y independently represents an oxygen atom, a sulfur atom or -NR'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R1 independently represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms, and
each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b" represents an integer in the range from 0 to 2, and
each sum of "a" + "b" per boron atom is in the range from 1 to 2. Yet a further aspect of this invention is compounds comprising at least one moiety represented by formula (IV) and (IIB):
R2 2BYR1 (IV) and
(B(R2)a(YR1)bY)3 (IIB),
wherein
each Y independently represents an oxygen atom, a sulfur atom, or - R'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R1 independently represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising an alkynyl group, a benzyl group or one or more hetero atoms,
each "a" and "b" represents zero or 1, and
each sum of "a" + "b" per boron atom is equal to 1 or 2, preferably 1.
Another aspect of this invention is methods for cross-coupling organic compounds comprising reacting the above-described mixture, anion and/or compound with at least one organic compound having at least one CI, Br, I, nucleophilic leaving group or aldehyde substituent.
The organoboron products of the invention are useful for conducting coupling reactions and reactions with aldehydes. Due to their selectivity, such reactions may be conducted in protic solvents, such as water and alcohols, and sensitive functional groups in the reactants are maintained in the final product. The organoboron products are stable, so that they maintain their activity during storage.
Further details regarding the present invention are presented in the following detailed description of the invention.
Brief Description of the Drawings
Fig. 1 shows percent cross-coupling conversion for various catalysts based on the illustrated cross-coupling reaction according to the invention.
Detailed Description of the Invention Definitions of terms used herein
The abbreviations used herein are defined in the following table:
The term "metalated" means that the compound that is the subject of this adjective is bonded, coordinated or complexed with a metallic cation or cationic complex. The term "protic" or "protic hydrogen atom(s)" refers to acidic hydrogen atom substituents (i.e., hydrogen atoms the protons of which may be removed through contact with a Lewis base). In general, hydrogen atoms not attached to carbon atoms may be considered protic. Examples of protic hydrogen atoms include the hydrogen atoms of carboxylic acids, aldehydes, phenols, alcohols, and amines. The expression, "standard oxidation potential" refers to the oxidation potential measured at pH 14 under standard temperature and concentration conditions. The
oxidation potential is, by definition, the exact opposite of the standard reduction potential reported in the literature (e.g., a reduction potential of - 1.0 V equals an oxidation potential of +1.0 V). Examples of the reduction potentials for metals and metal complexes may be found in Annex VI, page 1843, of Hollemann-Wiberg, LEHRBUCH DER ANORGANISCHEN CHEMIE, 101ST edition (Walter de Gruyter, 1995).
The expression (B(R2)a(YR1)bY)3 refers to a cyclic structure of type
([B(R2)a(YR1)bY][B(R2)c(YR1)dY][B(R2)e(YR1)fYR1]) wherein a+b and c+d and e+f independently is in the range of 1 to 2 and each a,b,c,d,e, and f independently represents an integer in the range of 0 to 2. Unless stated otherwise, the expression "hetero atoms" as used herein refers preferably to the atoms N, O, S, P, B, Si, and Se. More preferred hetero atoms are N, O, S, and P.
Boron reagent
Boron-containing reagents of formulae (IA) and (IB) are reacted with organic compounds having CI, Br, I, and/or nucleophilic leaving groups to make boron- containing compounds.
The organic moieties R1 and R' of formulae (IA) and (IB) may be selected from a wide range of moieties having at least 1 , preferably at least 2, more preferably at least 3, and even more preferably at least 4 up to 15, more preferably up to 10, and even more preferably up to 8, carbon atoms and, optionally, one or more hetero atoms. Preferred moieties may be selected from saturated or unsaturated, straight or branched, aliphatic groups, cyclic groups or combinations of the aforementioned aliphatic and cyclic groups. The cyclic groups may be monocyclic or polycyclic, saturated or unsaturated, carbocyclic or heterocyclic ring structures. The polycyclic ring structures may be fused ring structures, bridged ring structures and rings sharing one atom in common preferably comprising up to 3, more preferably up to 2, rings. The aliphatic and/or cyclic moiety may have one or more substituents.
The hetero atoms may be present as chain and/or ring member and/or
substituent. Together with the carbon atoms, the hetero atoms may, for example, form ethers, ketones, amides, amines, nitro, cyano, esters, sulfonyl, etc., which are preferably protected if they would otherwise contain an acidic hydrogen atom, CI, Br,
I or nucleophilic leaving group. Some or all hydrogen atoms may be replaced by fluorine atoms.
The organic moiety preferably does not contain protic (i.e., acidic) hydrogen atoms and preferably does not have CI, Br, I, or nucleophilic leaving group
substituents. The organic moiety may be saturated or unsaturated, but is preferably saturated.
Examples of preferred R1 groups include ethyl, ^-propyl, isopropyl, «-butyl, sec-butyl, t-butyl, «-pentyl, «-hexyl, «-heptyl, «-octyl, «-nonyl, «-decyl, and n- dodecyl and the foregoing substituted with one or more substituents selected from the group methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl, and t-butyl. For various reasons including cost, availability and safety, unsubstituted «-butyl, sec-butyl, t-butyl, «-pentyl, «-hexyl, «-heptyl, and «-octyl are particularly preferred.
Examples of preferred R' groups include the above preferred R1 groups and methyl. The Cat of formula IA is any cation that does not negatively interfere with, or detract from, the desired reactions and reaction products. Cat may be selected from alkali metal cations such as Li+, Na+, and K+, alkaline earth metal cations such as Mg2+ and Ca2+, and quaternary amines such as tetralkyl ammonium compounds wherein the alkyl groups have 1 to 4, preferably 1-2, carbon atoms, such as N(«-Bu)4 + and mixtures thereof.
The value of "n" in Formulae (IB) corresponds to the valence, or charge, of the cation(s). When the salt of formula (IB) contains a mixture of cations having different valences or charges, "n" may have a fractional value representing the molar average charge of the cation mixture. Metals and Metal Complexes
The metals and metal complexes used in the process according to this invention may be any metal having a standard oxidation potential greater than the oxidation potential of the boron-containing reagent. The metals and metal complexes preferably have a positive standard oxidation potential at pH 14, more preferably a standard oxidation potential at pH 14 not less than 0.1 V, more preferably not less than 0.4 V,
even more preferably not less than 0.7 V, yet more preferably not less than 1 V, even more preferably not less than 1.5 V, and still more preferably not less than 2 V.
The metals are preferably in the zero (i.e., elemental) oxidation state when it is brought into contact with the other reactants. Preferred metals include Mg, Al, Ca, Zn, K, Li, and Na. The metals and metal complexes may be brought into contact with the other reactants in the form of solid metal turnings, shavings or nanoparticles.
The metal complexes are preferably complexes of metals with a ligand. The ligand is an electron donor (i.e., Lewis base) ligand capable of donating a pair of electrons to a metal ion capable of accepting the electrons as a Lewis acid to form a coordination bond. Examples of suitable ligands include N(R')3, 0(R')2, OOC-R', P(0)(R')3, P(R' )3, and multidentate ligands having two or more of the foregoing ligands, preferably bonded to the same or adjacent carbon atoms of an organic compound molecule, wherein each R' independently has the same meaning, including preferred meanings, as defined above. Examples of suitable ligands include PPh3, NEt3, imidazole, pyridine, acetate, and ethers. Multidentate ligands based on one or more of the aforementioned ligands are preferred. Suitable preferred metals include transition elements, such as Co, Cu, Fe, Cr, Mn, Mo, Os, Re and Ru, which have an oxidation state of at least +1.
The metal and/or metal complex is preferably introduced into the reaction mixture when the other reactants are already present in admixture with each other, preferably in a solvent. An amount of metal and/or metal complex is introduced which is preferably sufficient to drive the reaction to completion. This can generally be assured by providing an excess amount of metal and/or metal complex, so that solid metal and/or metal complex remains in the reaction mixture when no further reaction activity is observed.
Organic compound
The substrate for the reaction is at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent. Each nucleophilic leaving group is preferably selected from the group consisting
of -OS(0)2-RA, -N=N-RB, -OP(0)(ORc)2, -OC(0)RD, -SRE, and -N(RF)3 RG, wherein RA, Rc, RD, RE, and RF each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group preferably has
B G
from 1 up to 10, preferably up to 7, carbon atoms, and R and R each represent BF4. Preferred hydrocarbyl groups include methyl, branched-chain and straight-chain aliphatic hydrocarbons such as ethyl, propyl, isopropyl, «-butyl, sec-butyl and t-butyl, and aromatic hydrocarbons such as phenyl and benzyl. Preferred fluorocarbyl groups include -(CF2)mCF 3, wherein "m" represents an integer in the range from zero to 4 and fluorinated aryl groups, such as fluorinated benzyl groups.
Preferred nucleophilic leaving groups include triflates (-OS(0)2CF3); mesylates (-OS(0)2CH3); nonaflates (-OS(0)2(CF2)3CF3); tosylates (-OS(0)2C6H5CH3);
diazonium salts such as ArN2BF4, wherein Ar represents an aryl group such as phenyl, benzyl, tolyl, xylyl, or naphthyl; acetate; pivalate; thiomethyl; and thioaryl, such as thiobenzyl.
Preferred organic compounds may be represented by formula (V):
R5LP (V)
wherein R5 represents an organic residue comprising one or more carbon atoms and, optionally, one or more hetero atoms;
L represents CI, Br, I, or a nucleophilic leaving group, such as the preferred
nucleophilic leaving groups described above; and
"p" represents an integer in the range from 1 up to 10, preferably up to 4, more preferably up to 2, and even more preferably up to 1.
The organic residue, R5, preferably does not comprise protonated hetero atoms such as, for example, OH, H, or SH and preferably comprises one or more cyclic groups and/or one or more aliphatic groups.
The cyclic groups may comprise carbocyclic groups, such as cycloalkyl groups and aryl groups, and heterocyclic groups, such as heteroaryl groups and partially or fully saturated heterocyclic compounds. Preferred cyclic groups have at least 4, more preferably at least 5, and even more preferably at least 6, up to 20, more preferably up to 15, and even more preferably up to 10, carbon atoms and optionally from 1 preferably up to a number of hetero atoms equal to the number of carbon atoms in the cyclic group. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The cyclic group may comprise a
monocyclic or polycyclic ring system. The polycyclic ring system may comprise fused ring systems, bridged ring systems and rings having one atom in common.
Preferred carbocyclic groups are aryl cycloalkyl groups,and cycloalkenyl groups, such as phenyl groups, napththalene rings, cyclohexyl groups, cyclohexenyl groups, cyclopentyl groups, cyclopentenyl groups, etc.
Preferred heterocyclic groups include heteroaryl groups having 5, 6, or 7 ring members and 1, 2, or 3 hetero atoms. Examples of heterocyclic groups containing one or more nitrogen atoms as ring members include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, isoxazolyl, furazanyl, pyridinyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, morpholinyl or morpholino, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalizinyl, naphthyridinyl, carbazolyl, phenazinyl, phenanthradinyl, acridinyl, phenothiazinyl, perimidinyl, phenanthrolinyl, and phenoxazinyl. Examples of oxygen-containing heterocyclic groups other than those previously mentioned among nitrogen atom-containing heterocyclic groups include furyl, pyranyl, isobenzofuranyl, chromenyl, chromanyl, iaochromanyl, and xanthenyl.
The aliphatic group preferably comprises at least 2, more preferably at least 3, and even more preferably at least 4, up to 20, more preferably up to 12, and even more preferably up to 8, and even more preferably up to 6, carbon atoms. The aliphatic group may be straight-chained or branched, may comprise one or more heteroatoms representing up to half, more preferably up to one-fourth, the total number of atoms in the aliphatic group, and may comprise one or more unsaturated bonds. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The unsaturated bonds are preferably double bonds and triple bonds. Preferred aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups. The aliphatic groups are preferably saturated (i.e., do not contain unsaturated bonds).
The substituents, when present, are preferably selected from among the aforementioned preferred R1 cyclic and aliphatic groups bonded directly to the aforementioned cyclic or aliphatic groups or bonded indirectly to the same via a Y
group as defined above. Preferred substituents also include fluorine atoms and nonprotic functional groups.
Preferred functional group substituents are nitrile, nitro, ester, amide, protected alcohol, protected amine and protected amide. The ester group is preferably represented by the formula -C(0)OR3 , wherein R3 is an organic moiety, which may be selected from each and every option presented for R1 of Formula (I) above.
Protected alcohol, protected amine and protected amide are alcohol, amine and amide groups in which each proton bonded to an oxygen atom or nitrogen atom has been replaced with a group that is less reactive than the proton and yet capable of being removed to permit reactions to take place on the respective groups. Suitable protecting groups for those functionalities are well known in the state of the art. A description of suitable protective groups is provided, for example, in "Protective groups in organic synthesis" T. W. Greene, P. G. M: Wuts, Wiley. An example is TIPS to protect alcoholic and phenolic OH groups. Reaction conditions
The syntheses of organoboron compounds is preferably conducted at a temperature in the range from -30°C, more preferably from -10°C, up to, but not including, the decomposition temperature of the reactant having the lowest
decomposition temperature. In most cases, the reaction may preferably be conducted at temperatures in the range from 10°C, more preferably from 20°C up to 50°C, more preferably up to 30°C, such as at ambient (e.g., room) temperature.
The reaction is generally conducted under the exclusion of oxygen, or air, in an nonprotic, preferably inert, solvent under an inert atmosphere, such as argon gas, until conversion is complete. Suitable inert nonprotic solvents include, but are not limited to, cyclic, linear or branched mono- or polyethers such as THF, Me-THF, dibutyl ether, diethylether, tert-butylmethylether, dimethoxyalkylether, and dimethoxyalkanes; thioethers such as dimethyl sulfide and dibutyl sulfide; tertiary amines such as triethylamine, and ethyldiisopropylamine; phosphines; aromatic hydrocarbons, such as benzene, toluene and xylene; heteroaromatic hydrocarbons such as pyridine, N- methyl -2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone ( EP), N-butyl-2-pyrrolidone ( BP); aliphatic hydrocarbons, such as pentane, hexane, or heptane; cycloalkyls such as cyclohexane; dialkyl sulfoxides such as dimethylsulfoxide, amides such as
dimethylformamide, Ν,Ν-dimethylacetamide and hexamethylphosphortriamide (HMPA); cyclic, linear or branched alkanes in which one or more hydrogen atoms are replaced by halogen atoms, such as dichloromethane, tetrachloromethane,
hexachloroethane; urea derivatives such as Ν,Ν'-dimethylpropylene urea (DMPU) and Ν,Ν,Ν',Ν'-tetram ethyl urea; acetonitrile; and CS2 either individually or two or more in combination. Cyclic ethers, such as THF and Me-THF, are preferred.
This reaction is preferably carried out in the substantial absence of protic solvents, such as water. Unless stated otherwise, the solvent has been dried to minimize the presence of protic solvents such as water. The reaction vessel, reactants and solvent are preferably dried or distilled before use to ensure that water is not present during the reaction.
Synthesis of the organoboron compounds is preferably conducted in the presence of LiX, wherein X represents halide selected from CI, Br, and I. X is preferably CI. LiX has an accelerating effect on the synthesis of the organoboron compounds. The reaction rate is generally sufficient without a further catalyst, so that in a preferred embodiment the reaction is carried out in the absence of a transition metal catalyst.
The reaction is preferably carried out in a one pot procedure. In other words, the reaction is preferably carried out by contacting a solution containing the organic compound substrate, at least one boron reagent and, preferably, LiX with the metal to generate the desired organoboron compound(s) in situ (i.e., without conducting transmetallation of the organic compound substrate in a separate step prior to reacting the metalated organic compound with a boron-containing compound).
Organoboron products
The process according to the invention produces organoboron compounds wherein the organic substrate molecules form bonds between the carbon atoms to which CI, Br, I, or an nucleophilic leaving group were attached and the boron atoms of the boron reagent to form various neutral or anionic species depending on the ratio of equivalents of the CI, Br, I, and nucleophilic leaving groups to boron atoms present in the reaction mixture and the nature of the solvent used to conduct the reaction.
The ratio of equivalents influences the degree to which the organic compound substrate is substituted on the boron-containing reagents. Increasing the ratio of
organic compound substrate to boron atoms increases the molar average number of organic compound substrate molecules bonded to the boron atoms of the boron- containing reagents. When the ratio of equivalents is greater than 1 : 1, a mixture of organoboron compounds may be produced having various degrees of organic compound substrate substitution.
When the organoboron product is neutral, the organoboron product may comprise a mixture of one or more components comprising the following moieties:
R2B(YR1)2,
R2 2BYRX,
R2 3B, and/or
(B(R2)a(YR1)bY)3,
wherein
each "a" and "b" represents an integer in the range from 0 to 2 and each sum of "a" + "b" per boron atom is 1 or 2.
In a preferred aspect of this invention, the neutral compounds may comprise moieties represented by formula (IV) and (IIB):
R2 2BYR1 (IV) and
(B(R2)a(YR1)bY)3 (IIB),
wherein
each Y and R1 have the same meaning as defined in formulae (IA) and (IB) above. Each R1 independently preferably represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety comprising an alkynyl group, a benzyl group or one or more hetero atoms, wherein the organic group is bonded to the boron atom of the moiety represented by formula (IIA) or (IIB) via a carbon - boron covalent bond, each "a" and "b" represents zero or 1, and
each sum of "a" + "b" per boron atom is equal to 1.
Conducting the reaction in nonprotic polar solvents tends to generate anionic organoboron species charge-balanced by cationic species generated in situ. This is in contrast to conducting the reaction in nonpolar solvents such as toluene, which tends to generate a greater proportion of neutral species. To maximize yield and reaction rates under mild conditions, the generation of anionic organoboron species in nonprotic polar solvents, such as THF, is preferred.
When the organoboron product is anionic and the ratio of equivalents of organic compound substrate to boron-containing reagent is greater than 1 : 1, the organoboron product may comprise a mixture of one or more of anionic components comprising the following moieties:
R^YR1^,
R2 2B(YR1)2,
R2 3B(YR1),
R2 4B, and/or
(B(R2)a(YR1)bY)3,
wherein
each Y, R1, and R2 have the same meaning as defined above,
each "a" and "b" represents an integer in the range from 0 to 2,
each sum of "a" + "b" per boron atom is in the range from 1 to 2, and
the sum of "a" + "b" per molecule is at least 4.
In a preferred embodiment, the product of the reaction is a mixture comprising components (A) and (B):
(A) at least one anion comprising at least one moiety represented by the formula (IIA)
R2 2B(YR1)2 (IIA) and/or
a compound or anion comprising at least one moiety represented by formula (ΠΒ)
(B(R2)a(YR1)bY)3 (ΠΒ) and
(B) at least one anion comprising at least one moiety represented by the formula (III)
R2 4B (III),
wherein
each Y and R1 have the same meanings as defined above in formulae (IA) and (IB), each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond, each "a" and "b" represents an integer in the range from 0 to 2,
each sum of "a" + "b" per boron atom is in the range from 1 to 2, and
the molar ratio of component (B) to component (A) is at least 1 : 100, preferably at least 1 :50, and more preferably at least 1 :20.
In the same or different preferred embodiment, the preferred anions comprise moieties represented by the formula (IIA) and/or (IIB):
R2 2B(YR1)2 (IIA) and/or
(B(R2)a(YR1)bY)3 (IIB),
wherein
each Y and R1 has the same meaning as in formulae (IA) and (IB) above. R1 preferably represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b" represents an integer in the range from 0 to 2,
each sum of "a" + "b" per boron atom is in the range from 1 to 2, and
the sum of "a" and "b" per formula (IIB) molecule is at least 4, preferably at least 5.
The anions are accompanied by a charge-balancing amount of cations. The cations comprise the metallic cations formed by oxidizing the metal during the reaction, cations introduced via salts of formula (IB), when present, and Li+ introduced via LiX.
The organoboron-containing mixtures, salts and compounds may be isolated and, if necessary, dried or dispersed or dissolved in a wide range of solvents. Once formed, the products are stable not only in the solvents used to synthesize the product, but also in a variety of protic solvents as well, such as water and various alcohols, for example.
End use applications
The above-described organoboron mixtures, anions and compounds are useful for conducting coupling reactions with electrophiles, such as the Suzuki-type cross- coupling reactions and, in particular, the Suzuki-Miy aura-type cross-coupling reactions. In a preferred embodiment, the electrophiles are organic compounds having at least one CI, Br, I, or nucleophilic leaving group. The nucleophilic atoms and groups react with the organoboron anions and compounds disclosed herein to make organic compounds that are larger and/or more complex than the organic compound substrate that was used to make the organboron anions and compounds. The electrophile may be reacted with the above-described organoboron compounds in the presence of a cross-coupling catalyst to couple the electrophile residue with the organo portion of the organoboron compound.
Due to their stability, the organoboron products may be used to conduct cross- coupling with organic compounds that have, in addition to the electrophilic atom(s) or group(s), functional groups having sensitive functional groups, such as -OH groups, carboxylic acid groups, and the like, without requiring replacement of the protic hydrogen atoms with protective groups prior to conducting the reaction. The choice of electrophiles is therefore much broader than the choice of organic compound substrates for synthesizing the organoboron compounds of the invention.
Examples of sensitive functional groups on the electrophile tolerated during cross-coupling include, for example, nitrile groups, -OH groups, acid groups, ester groups, amide groups, aldehyde groups, keto groups and cyano groups.
The ability to conduct such cross-coupling reactions with unprotected sensitive functional groups is a surprising and unexpected advantage over state of the art cross- coupling reactions.
Cross-coupling is conducted with a catalyst and a base. The cross-coupling catalyst and base is preferably selected from the types used in state of the art Suzuki- type, or in particular the Suzuki-Miyaura-type, cross-coupling reactions. Appropriate catalysts and bases are well-known. Preferred catalysts comprise one or more palladium or nickel atoms. Examples of preferred catalysts include PdCl2, Pd(PPh3)4, Pd(OAc)2> PdCl2, which surprisingly may be used without stabilizing ligands, and NiBr2(PPh3)4. An example of a base is a basic alkali metal salt, such as an alkali metal phosphate. An example is potassium phosphate.
The reaction conditions for conducting cross-coupling are the same as, or analogous to, the preferred conditions for synthesizing the organoboron mixtures, anions, and compounds according to the invention. Further details on how to conduct such cross-coupling reactions are provided in S. R. Chemler, D. Trauner, S. J.
Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544-4568; A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674 -688; G. A. Molander, B. Canturk, Angew. Chem. Int. Ed. 2009, 48, 9240 - 9261; and N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, which are incorporated herein by reference for their relevant disclosures. .
Exceptionally, aldehyde groups react with the organoboron via a secondary addition reaction to link the organo portion of the organoboron with the organic compound bearing the aldehyde via a secondary alcohol. When it is desired to link organic compounds via this route, the organic compound to be added to the organo portion of the organoboron compound does not need to undergo cross-coupling and therefore does not require an electrophilic atom or group substituent, nor cross- coupling catalyst or base. The invention is now illustrated by the following examples.
Example 1:
Preparation of ethyl 4-(l-phenylvinyl)benzoate (6i)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (78 mg, 3.2 mmol) and LiCl (93 mg, 2.2 mmol). The LiCl was dried in vacuo using a heat gun (450 °C, 5 min). After
addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). Stirring for 5 min was followed by addition of B(OBu)3 (230 mg, 1 mmol). Thereafter, the suspension was cooled to 0 °C, a solution of (l-bromovinyl)benzene (4d, 366 mg, 2 mmol) in THF (2 mL) was added and the reaction mixture was strirred for 30 min at 0 °C to make the arylvinylborates.
To demonstrate the suitability of the arylvinylborates for cross-coupling reactions, the supernatant solution was then cannulated dropwise into a new argon- flushed Schlenk flask charged with ethyl 4-bromobenzoate (7g, 1.6 mmol, 367 mg), PdCl2 (4 mol%, 14 mg), dppf (4 mol%, 44 mg) and Cs2C03 (652 mg, 2 mmol) in EtOH (4 mL) followed by stirring at 65 °C for 6 h. Subsequently, the reaction mixture was diluted with 5 mL EtOAc and quenched with brine (10 mL). The aqueous layer was extracted with CH2C12 (3x 15 mL). The combined organic phases were dried over Na2S04 and the solvent was removed in vacuo.
The crude product was purified by flash column chromatography (Si02, pentane/Et20 = 95:5) affording 6i as pale yellow solid (383 mg, 95%).
Example 2:
Preparation of 2-chloro-3-(3-thienyl)pyridine (6m)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (78 mg, 3.2 mmol) and LiCl (93 mg, 2.2 mmol). The LiCl was dried in vacuo using a heat gun (450 °C, 5 min). After addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). Stirring for 5 minutes was followed by addition of B(OBu)3 (230 mg, 1 mmol). Thereafter, the suspension was cooled to 0 °C, a solution of 3-bromothiophene (4h, 326 mg, 2 mmol) in THF (2 mL) was added and the reaction mixture was strirred for 30 min at 0 °C to make the thiophene- substituted borates.
To demonstrate the suitability of the thiophene- substituted borates for cross- coupling, the supernatant solution was then cannulated dropwise into a new argon- flushed Schlenk flask charged with 2-chloro-3-iodopyridine (7k, 1.6 mmol, 383 mg), PdCl2 (4 mol%, 14 mg), dppf (4 mol%, 44 mg) and Cs2C03 (652 mg, 2 mmol) in EtOH (4 mL) and DMF (1 mL) followed by stirring at 65 °C for 1 h. Subsequently,
the reaction mixture was diluted with 5 mL EtOAc and quenched with brine (10 mL). The aqueous layer was extracted with CH2CI2 (3x 15 mL). The combined organic phases were dried over Na2S04 and the solvent was removed in vacuo.
The crude product was purified by flash column chromatography (Si02, pentane/EtOAc = 9: 1 with 0.5% NEt3) affording 6m as pale yellow solid (291 mg, 93%).
Example 3
Preparation of organoborates
Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent) with various borates (0.33 equivalent) and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 20 minutes at 25°C in dry THF as the solvent. The reaction produced a reaction mixture containing reaction products in which the boron atom of the former borate reactant has from 1 to 4 o-xylene substituents bonded at the o-xylene 4-position and from 1 to 3 of the alkoxy or aceto groups of the organoborate was replaced by o-xylene at the o-xylene 4-position. The boron product was substantially anionic (i.e., boron with 4 subsituents) with Mg2+ generated via oxidation of the magnesium turnings as the primary cationic counter-ion. The most prevalent organoborate anion had two o-xylene groups, wherein one of the o-xylene groups replaced an alkoxy or acetoxy substituent formerly on the borate reactant.
The percent conversions of the substrate to the organoborate (i.e., yield) for the respective borate reactants tested are shown in Table 1.
Table 1
Preparation of organoborates using various borate sources
Entry Borate Product
Reactant (conversion)
1 B(OMe)3 33%
2 B(OEt)3 49%
3 B(OiPr)3 51%
4 B(OBu)3 64%
5 B(OAc)3 43%
6 Na+ B(OMe)4 " 28%
Li B(OMe)4 41%
As shown in table 1, the selection of borate additive influences the conversion rate.
The conversion rate is also affected by the ratio of equivalents between organohalide substrate and the borate reactant. Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent, referred to below as the "substrate") with tributylb orate (referred to below as the "borate") and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 30 minutes at 25°C in dry THF as the solvent. The respective substrate to borate equivalent ratios and the percent conversions of the 4-bromo-o-xylene to the organoborate are shown in Table 2.
Table 2
Preparation of organoborates using various ratios of reactants
Entry Substrate / Borate Ratio Organoborate
(conversion)
1 0.25 eq 71%
2 0.33 eq 79%
3 0.5 eq 83%
4 1.0 eq 82%
Example 4:
Preparation of organoborates using Li, Na, Ca, K, Al and Zn
Tributylb orate (0.5 equivalent) and Li, Na and K are reacted with
4-bromoxylene (1 equivalent) in the presence of LiCl in dry THF according to the conditions shown in entries 1 to 3 of Table 3.
Tributylb orate (0.5 equivalent) and Ca, Al and Zn are reacted with 1-bromo- bis(trifluoromethyl)-benzene (1 equivalent) in the presence of LiCl in dry THF according to the conditions shown in entries 4 to 6 of Table 3.
Table 3
1 Li >95% 0.5 25
2 Na >95% 12 25
3 K >83% 8 25
4 Ca >90% 2 25
5 Al >95% 0.5 65
6 Zn 84% 12 65
As can be seen from the data in the above table, the metal used to drive the reaction may be selected from any one of the metals listed in Table 3. Of those metals, the highest reaction rates and yields for this reaction are obtained with Li and Al followed by Ca and Na. Yields greater than 80%> are attained for K and Zn in 12 hours or less.
Example 5
Synthesis of Ethyl 4-(3,4-dimethylphenyl)-benzoate (6a)
Tributylb orate (0.5 equivalent) and Mg are reacted with 4-bromoxylene (1 equivalent) in the presence of LiCl in dry THF at 25°C for 30 minutes to make the xylene- substituted boron compound with 90% yield. The reaction mixture is then reacted with ethyl 4-iodophenylcarboxylate (4-iodophenylpropionate) in a 3 : 1 mixture of THF to methanol in the presence of 4 mol% catalyst selected according to Fig. 1 and 1 equivalent potassium phosphate for 12 hours at 65°C to form the title compound 6a
As shown in Fig. 1, the organoborates of the invention can be cross-coupled to produce the desired product in high yield using a wide variety of palladium and nickel catalysts, including catalysts in which the metal atom is not stabilized by ligands such as dppp, dppe, dba, TTMPP, and acac.
Example 6
To demonstrate the suitability of the organoborates for cross-coupling functionalized organic compounds, functionalized aryl bromides 4a-e are reacted with magnesium turnings (1.6 equiv) in the presence of B(OBu)3 (0.5 equiv) and LiCl (1.1 equiv) in a 1 : 1 mixture of THF and ethanol providing the corresponding arylborates 5a-e in ca. 90% yield. Subsequent Suzuki type cross-couplings with aryl iodides or bromides in a 1 : 1 mixture of THF and ethanol or DMF at 65°C according to conditions [a] to [d] described in the footnotes below furnished the polyfunctional aromatics 6b-k in 79-96% yield (Table 4, entries 1-10).
Table 4
Preparation of poly substituted aromatics via functionalized arylborates of type 5 prepared by direct magnesium insertion in the presence of B(OBu)3
[a] Obtained after cross-coupling in 1 : 1 mixture of THF and ethanol in the presence of Pd(PPh3)4 (4 mol%) as Pd catalyst and with Cs2C03 (1 equiv) as base for 2 h
[b] Obtained after cross-coupling in DMF in the presence of PdCl2(dppf) (4 mol%), as Pd catalyst and with Cs2C03 (2 equiv) as base for 12 h
[c] Obtained after cross-coupling in 1 : 1 mixture of THF and ethanol in the presence of PdCl2 (4 mol%) as Pd catalyst and with K3P04 (2 equiv) as base for 2 h
[d] Obtained after cross-coupling in 1 : 1 mixture of TFIF and ethanol in the presence of PdCl2(dppf) (4 mol%) as Pd catalyst and with Cs2C03 (1 or 2 equiv) as base for 6 h
As can be seen from the results shown in Table 4, compounds may be synthesized with a variety of sensitive functional group substituents without intervening protection and deprotection of those substituents, thereby simplifying the
process for obtaining those compounds and reducing the quantity of wasteful byproducts.
Example 7
Synthesis of polysubstituted heteroaromatic and aromatic compounds starting from heteroaryl and benzyl compounds
Functionalized heteroaryl bromides and benzyl chlorides 4g-j may also be reacted with magnesium in the presence of B(OBu)3 to furnish, after subsequent cross-coupling with substituted aryl iodides or bromides 7g and 7j-m in a 1 : 1 mixture of THF and ethanol or DMF at 65°C according to conditions [a] to [d] described in the footnotes below, polyfunctional aromatics 61-p (Table 5, entries 1-5).
Table 5
Preparation of polysubstituted heteroaromatics and aromatics via functionalized heteroaryl and benzylborates prepared by direct magnesium insertion in the presence of B(OBu)3.
Conditions
Entry Substrate Electrophile Product (Yield, %)
[a] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2C03 (2 equiv), THF/EtOH (1 : 1), DMF, 65 °C, 12 h)
[b] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2C03 (2 equiv), THF/EtOH (1 : 1), DMF, 65 °C, 1 h)
[c] Obtained after Pd-catalyzed cross-coupling (Pd(PPh3)4 (4 mol%), K3P04 (2 equiv), THF/EtOH (1 : 1), 65 °C, 2 h)
[d] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2C03 (2 equiv), THF/EtOH (1 : 1), 65 C, 6 h)
As can be seen from the results in Table 5, functionalized heteroaryl bromides or benzyl chlorides 4g-j react outstandingly fast with magnesium in the presence of B(OBu)3 and furnish after subsequent cross-coupling with substituted aryl iodides or bromides 7g and 7j-m the desired polyfunctional aromatics 61-p (Table 5, entries 1- 5).
In the absence of borate, only dimeric products can be obtained by the direct magnesium insertion into benzylic carbon-halide bonds. Surprisingly, no dimeric homo-coupling product was observed during the preparation of benzylborates.
The obtained product is water-stable, hence convenient for subsequent reactions.
Example 8
Preparation of alkylborates and allylborates by direct magnesium insertion
Functionalized primary and secondary alkylborates as well as allylborates may also be prepared by direct magnesium insertion as shown in Table 6 below.
Magnesium metal is contacted with respective substrate mixed with 0.5 equivalent tributylb orate per equivalent of the substrate and lithium chloride in THF to make the organoborate. The results are shown in Table 6.
Table 6
Preparation of alkylborates, allylborates and benzylborate by direct
magnesium insertion
Entry Substrate Conditions Borate (Yield, %)
(t , T)
Et02C ^
1 h, 25 °C Et02C ^^B DBu)
8a 9a (>90)
Me Me
EtO,C EtOpC
Br 1 h, 25 °C 2 B(OBu)
8b 9b (>90)
P Ph
EtOpC EtO,C
30 min, 0 °C 2 B(OBu)
8c 9c >90)
, Br B(OBu)
2
30 min, 0 °C
8e 9e (>85)
CQ2Et C02Et
,Br 30 min, 0 °C
8f 9f (>85)
As shown by Table 6, functionalized primary and secondary alkyl bromides 8a- d reacted efficiently under standard conditions with magnesium turnings in the presence of LiCl and B(OBu)3 to produce the corresponding alkylborates 9a-d (Table 6, entries 1-4). Also, otherwise difficult to prepare allylborates 9e-f could efficiently be prepared via the described method (Table 6, entries 5 and 6).
Example 9
Preparation of polysubstituted organic compounds starting from 4-bromophenol substrate without the use of protective groups
4-Bromophenol in THF is converted to the sodium salt by introducing sodium hydride (NaH) and allowing the reaction to take place for 20 minutes at 0°C. 0.5 equivalent of tributylb orate is then added per equivalent of the resulting phenolic salt product and the temperature of the solution is raised to 25°C over a period of one hour.
Lithium chloride is then added to the above room temperature solution and the solution is contacted with magnesium metal turnings for 2 hours at 25°C to form the arylborates. The arylborates are then combined with 1 equivalent of 4-cyano-2-iodo- aniline (electrophile) per 0.5 equivalent of the arylborate, 2 equivalent cesium carbonate (base) per equivalent of electrophile and enough methanol to provide a mixture with THF in a 1 : 1 ratio and the components of this mixture are reacted in the presence of 4 mol% Pd(PPh3)4 (catalyst) for 1 hour at 65°C.
The above reaction sequence produces 4-cyano-2-(4-hydroxyphenyl)aniline with a yield of 75%.
Example 10
Preparation of ethyl 4-[3,5-6is(trifluoromethyl)phen-l-yl)benzoate (15a) via direct aluminium insertion and subsequent Pd-catalyzed cross-couplings
The substrate l-bromo-fos(trifluoromethyl)benzene 4a is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4a in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4a at 65°C for 1 h to make the /s(trifluoromethyl)phenylborate 5a in ca. 90% yield.
The arylborate 5a is then subjected to Pd-catalyzed cross-coupling with ethyl 4- iodobenzoate (7a); together with 2 equivalent cesium carbonate (base) per equivalent of 7a in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% Pd(PPh3)4 (catalyst) at 65 °C for 12 h to produce the title polyfunctional arene 15a in 68% yield.
Example 11
Preparation of ethyl 3-(4-cyanobenzyl)-4-ethoxycarbonylbenzoate (15b) via direct aluminium insertion and subsequent Pd-catalyzed cross-couplings
The substrate ethyl 2-bromo-4-ethoxycarboxybenzoate 4k is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4k in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4k at 65°C for 7 h to make the 2,5-di(ethoxycarboxy)phenylborate 5k in ca. 90% yield.
The arylborate 5k is then subjected to Pd-catalyzed cross-coupling with 4- bromobenzonitrile (7j); together with 2 equivalent cesium carbonate (base) per equivalent of 7j in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% PdCl2(dppf) (catalyst) and DMF at 65 °C for 12 h to produce the title polyfunctional arene 15b in 73% yield.
Example 12
Preparation of a secondary alcohol 14 via addition of arylborate 13 to a benzaldehyde derivative (7n) 4-bromo-o-xylene (substrate) is reacted with 0.5 equivalent of tributylb orate per equivalent of substrate andl .6 equivalent magnesium turnings per equivalent of substrate in the presence of 1.1 equivalent of LiCl per equivalent of substrate for 30 minutes at 25°C in dry THF as the solvent. 0.6 equivalent of the arylborate product is then reacted with 1 quivalent of 4-chlorobenzaldehyde (7n) for 1 h at 25°C to form 1- (3,4-dimethylphenyl)-l-(4-chlorophenyl)methanol (14) with a yield of 81%.
The aldehyde addition reaction proceeds without the use of catalysts or promoters.
Claims
A process for making boron-containing organic compounds comprising reacting at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent with at least one boron-containing reagent represented by the chemical formula (IA) and/or (IB):
B(YR1)3 (IA)
[Cat]n+[B(YR1)4-]„ (IB) in the presence of at least one oxidizable metal and/or oxidizable metal complex having a positive standard oxidation potential measured at pH 14,
wherein
each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
Cat is a cation or mixture of cations, and
n is a positive number in the range from 1 to 3.
The process according to claim 1, wherein the oxidizable metal and/or metal complex has a standard oxidation potential measured at pH 14 not less than +0.1 V.
The process according to claim 1 or 2, wherein the process is carried out in the presence of LiX, wherein X represents CI, Br or I.
The process according to any one of the preceding claims, wherein each nucleophilic leaving group is selected from the group consisting
of -OS(0)2-RA, -N2RB, -OP(0)(ORc)2, -OC(0)RD, -SRE, and -N(RF)3 RG, wherein RA, Rc, RD, RE, and RF each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group has from 1 to 10 carbon atoms, and R B and R G each represent BF4. A mixture comprising components (A) and (B):
1
(A) at least one anion comprising at least one moiety represented by the formula (IIA)
R2 2B(YR1)2 (IIA) and/or
a compound or anion comprising at least one moiety represented by formula (ΠΒ)
(B(R2)a(YR1)bY)3 (ΠΒ) and
(B) at least one anion comprising at least one moiety represented by the formula (III)
R2 4B (III),
wherein
each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R1 and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety bonded to the boron atom of the anion or compound via a carbon - boron covalent bond,
each "a" and "b" represents an integer in the range from 0 to 2,
each sum of "a" + "b" per boron atom is in the range from 1 to 2, and the molar ratio of component (B) to component (A) is at least 1 : 100.
6. The mixture of claim 5 further comprising at least one metal cation selected from the group consisting of Mg , Al , Ca , Zn , K , Li , and Na .
7. An anion comprising at least one moiety represented by the formula (IIA):
R2 2B(YR1)2 (IIA) or at least one compound or anion comprising at least one moiety represented by formula (ΠΒ)
(B(R2)a(YR1)bY)3 (ΠΒ),
wherein
2
each Y independently represents an oxygen atom, a sulfur atom or - R'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R1 independently represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms, and
each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms,
each "a" and "b" represents an integer in the range from 0 to 2, and
each sum of "a" + "b" per boron atom is in the range from 1 to 2.
8. A compound comprising at least one moiety represented by formula (IV) or (IIB)
R2 2BYR1 (IV) or
(B(R2)a(YR1)bY)3 (IIB),
wherein
each Y independently represents an oxygen atom, a sulfur atom, or -NR'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,
each R1 independently represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,
each R2 independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising an alkynyl group, a benzyl group or one or more hetero atoms,
each "a" and "b" represents zero or 1, and
each sum of "a" + "b" per boron atom is equal to 1.
9. The anion of claim 7 or the compound of claim 8, wherein each R1 is ft-butyl or sec-butyl.
10. The anion of claim 7 or 9 or the compound of claim 8 or 9, wherein the organic moiety of R2 comprises at least one heterocyclic ring, wherein the carbon atom bonded to boron is a member of the heterocyclic ring.
11. The anion of claim 7, 9 or 10 or the compound of any one of claims 8 to 10, wherein R2 comprises at least one ester group, aldehyde group, amide group or cyano group.
12. A method for cross-coupling organic compounds comprising reacting the
mixture according to claim 5 or 6, the anion according to claim 7, 9, 10 or 11, and/or the compound according to any one of claims 8 to 11 with at least one organic compound having at least one CI, Br, I, nucleophilic leaving group or aldehyde substituent.
13. The method according to claim 12, wherein the process is conducted in the presence of a catalyst and a base.
14. The method according to claim 13, wherein the catalyst comprises palladium or nickel.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201061425815P | 2010-12-22 | 2010-12-22 | |
US61/425,815 | 2010-12-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012085170A2 true WO2012085170A2 (en) | 2012-06-28 |
WO2012085170A3 WO2012085170A3 (en) | 2012-10-26 |
Family
ID=45531360
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2011/073716 WO2012085170A2 (en) | 2010-12-22 | 2011-12-22 | Process for making organoboron compounds, products obtainable thereby, and their use |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2012085170A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554094A (en) * | 2013-11-19 | 2014-02-05 | 郑州西格玛化工有限公司 | Method for preparing 2,2'-bipyridyl-4,4-(5-hexyl-2-thiophene) |
CN112004807A (en) * | 2018-06-01 | 2020-11-27 | 自体吞噬科学有限公司 | Novel compounds and pharmaceutical compositions comprising said compounds |
RU2793138C2 (en) * | 2018-06-01 | 2023-03-29 | Аутофэджисайенсиз Инк. | New compounds and pharmaceutical composition containing them |
-
2011
- 2011-12-22 WO PCT/EP2011/073716 patent/WO2012085170A2/en active Application Filing
Non-Patent Citations (6)
Title |
---|
A. C. FRISCH; M. BELLER, ANGEW. CHEM. INT. ED, vol. 44, 2005, pages 674 - 688 |
G. A. MOLANDER; B. CANTURK, ANGEW. CHEM. INT. ED., vol. 48, 2009, pages 9240 - 9261 |
HOLLEMANN-WIBERG: "LEHRBUCH DER ANORGANISCHEN CHEMIE", 1995, pages: 1843 |
N. MIYAURA; A. SUZUKI, CHEM. REV., vol. 95, 1995, pages 2457 - 2483 |
S. R. CHEMLER; D. TRAUNER; S. J. DANISHEFSKY, ANGEW. CHEM. INT. ED, vol. 40, 2001, pages 4544 - 4568 |
T. W. GREENE; P. G. M: WUTS: "Protective groups in organic synthesis", WILEY |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554094A (en) * | 2013-11-19 | 2014-02-05 | 郑州西格玛化工有限公司 | Method for preparing 2,2'-bipyridyl-4,4-(5-hexyl-2-thiophene) |
CN103554094B (en) * | 2013-11-19 | 2016-04-27 | 郑州西格玛化工有限公司 | One prepares 2, the method for 2 '-dipyridyl-4,4 '-(5-hexyl-2-thiophene) |
CN112004807A (en) * | 2018-06-01 | 2020-11-27 | 自体吞噬科学有限公司 | Novel compounds and pharmaceutical compositions comprising said compounds |
JP2021534072A (en) * | 2018-06-01 | 2021-12-09 | オートファジーサイエンシーズ インコーポレイテッド | Novel compounds and pharmaceutical compositions containing them |
EP3805210A4 (en) * | 2018-06-01 | 2022-01-19 | Autophagysciences, Inc | Novel compound and pharmaceutical composition comprising same |
US11407744B2 (en) | 2018-06-01 | 2022-08-09 | Autophagysciences Inc. | Compound and pharmaceutical composition comprising same |
JP7177577B2 (en) | 2018-06-01 | 2022-11-24 | オートファジーサイエンシーズ インコーポレイテッド | NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
RU2793138C2 (en) * | 2018-06-01 | 2023-03-29 | Аутофэджисайенсиз Инк. | New compounds and pharmaceutical composition containing them |
CN112004807B (en) * | 2018-06-01 | 2023-07-18 | 自体吞噬科学有限公司 | Compounds and pharmaceutical compositions comprising the same |
Also Published As
Publication number | Publication date |
---|---|
WO2012085170A3 (en) | 2012-10-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6294314B2 (en) | Phosphine coordinated palladium sulfonate palladacycle | |
JP5489987B2 (en) | Bisamido zinc base | |
JP6157358B2 (en) | Organozinc complexes and methods for making and using organozinc complexes | |
Dubey et al. | Trinuclear complexes of palladium (ii) with chalcogenated N-heterocyclic carbenes: catalysis of selective nitrile–primary amide interconversion and Sonogashira coupling | |
Xu et al. | C–C bond cleavage in acetonitrile by copper (II)–bipyridine complexes and in situ formation of cyano-bridged mixed-valent copper complexes | |
Sharma et al. | Half-sandwich (η 5-Cp*) Rh (iii) complexes of pyrazolated organo-sulfur/selenium/tellurium ligands: efficient catalysts for base/solvent free C–N coupling of chloroarenes under aerobic conditions | |
EP3559012B1 (en) | Metal organic compounds | |
CN113754689B (en) | Nickel-catalyzed asymmetric hydroamination method for olefin | |
Shi et al. | Syntheses and structures of two anion-templated dinuclear cadmium complexes with diamino-binaphthyl Schiff bases as ligands | |
WO2006128097A1 (en) | Nucleophilic heterocyclic carbene derivatives of pd(acac)2 for cross-coupling reactions | |
Kumar et al. | PCP pincer carbene nickel (II) chloride, hydride, and thiolate complexes: hydrosilylation of aldehyde, ketone, and nitroarene by the thiolate complex | |
Lee et al. | A highly effective azetidine–Pd (II) catalyst for Suzuki–Miyaura coupling reactions in water | |
WO2012085169A1 (en) | Metallic amidoborates for functionalizing organic compounds | |
CN101184711A (en) | Nucleophilic heterocyclic carbene derivatives of pd(acac)2 for cross-coupling reactions | |
WO2012085170A2 (en) | Process for making organoboron compounds, products obtainable thereby, and their use | |
CN103748065B (en) | The manufacture method of 2-alkenyl amine compound | |
Kliś et al. | Organoboron Compounds in Visible Light-Driven Photoredox Catalysis | |
WO2022043993A1 (en) | Pcnhcp metal complexes and uses thereof | |
EP3072590B1 (en) | Hydrogen oxidation catalyst | |
GB2486631A (en) | Phenol/quinone boronic acids/esters and method of preparation thereof | |
KR101654787B1 (en) | Catalyst Composition Comprising Palladium Ketoiminate Complex and Preparation Method for Cross-Coupling Compound Using the Composition | |
CN111788001B (en) | Method for decomposing ammonia and ruthenium complex | |
CN111807971B (en) | Alkylation synthesis method for in-situ catalysis of alcohols | |
US20230095372A1 (en) | Multicyclic carbocation and carboradical compounds and methods of use | |
CN110605143B (en) | Application of organic iron salt as catalyst in synthesis of alkyl boron ester compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11813329 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 11813329 Country of ref document: EP Kind code of ref document: A2 |