WO2008134890A1 - Methods for preparing diorganozinc compounds - Google Patents
Methods for preparing diorganozinc compounds Download PDFInfo
- Publication number
- WO2008134890A1 WO2008134890A1 PCT/CA2008/000864 CA2008000864W WO2008134890A1 WO 2008134890 A1 WO2008134890 A1 WO 2008134890A1 CA 2008000864 W CA2008000864 W CA 2008000864W WO 2008134890 A1 WO2008134890 A1 WO 2008134890A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- carboxylic acid
- alkyl
- formula
- chosen
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 160
- 238000000034 method Methods 0.000 title claims abstract description 83
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 34
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 9
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 9
- -1 -OH Chemical group 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 125000005353 silylalkyl group Chemical group 0.000 claims description 28
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 25
- 125000006737 (C6-C20) arylalkyl group Chemical group 0.000 claims description 23
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 23
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 23
- 125000006734 (C2-C20) alkoxyalkyl group Chemical group 0.000 claims description 22
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 14
- 230000003197 catalytic effect Effects 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 12
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000004001 thioalkyl group Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 11
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 239000004202 carbamide Substances 0.000 claims description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 11
- 150000001975 deuterium Chemical group 0.000 claims description 11
- 229910052805 deuterium Inorganic materials 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 11
- 239000002244 precipitate Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 229940124530 sulfonamide Drugs 0.000 claims description 11
- 150000003462 sulfoxides Chemical class 0.000 claims description 11
- 229910052722 tritium Inorganic materials 0.000 claims description 11
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229960004132 diethyl ether Drugs 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 10
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 10
- 239000000758 substrate Substances 0.000 claims description 10
- 150000003456 sulfonamides Chemical class 0.000 claims description 10
- 150000001241 acetals Chemical class 0.000 claims description 9
- 150000003457 sulfones Chemical class 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 8
- 150000002466 imines Chemical class 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000007791 liquid phase Substances 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 4
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000006880 cross-coupling reaction Methods 0.000 claims description 4
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 4
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 150000001414 amino alcohols Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- DTGKSKDOIYIVQL-MRTMQBJTSA-N Isoborneol Natural products C1C[C@@]2(C)[C@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-MRTMQBJTSA-N 0.000 claims description 2
- 238000006564 Metalla-aza-Claisen rearrangement reaction Methods 0.000 claims description 2
- 125000005595 acetylacetonate group Chemical group 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- 125000000746 allylic group Chemical group 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 claims description 2
- 238000010664 carbozincation reaction Methods 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000005888 cyclopropanation reaction Methods 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims description 2
- 238000006735 epoxidation reaction Methods 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 claims description 2
- 150000008300 phosphoramidites Chemical class 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 229910052723 transition metal Inorganic materials 0.000 claims description 2
- 150000003624 transition metals Chemical class 0.000 claims description 2
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 8
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 239000011701 zinc Substances 0.000 abstract description 49
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 18
- 150000004795 grignard reagents Chemical class 0.000 abstract description 8
- 239000007818 Grignard reagent Substances 0.000 abstract description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract 2
- 229910052783 alkali metal Inorganic materials 0.000 abstract 2
- 150000001340 alkali metals Chemical class 0.000 abstract 2
- 229910052725 zinc Inorganic materials 0.000 abstract 2
- 101001122476 Homo sapiens Mu-type opioid receptor Proteins 0.000 abstract 1
- 102100028647 Mu-type opioid receptor Human genes 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 150000003752 zinc compounds Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 13
- 239000011777 magnesium Substances 0.000 description 12
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical compound [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000011592 zinc chloride Substances 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 4
- 125000002524 organometallic group Chemical group 0.000 description 4
- 150000003751 zinc Chemical class 0.000 description 4
- 241000819038 Chichester Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910009369 Zn Mg Inorganic materials 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 3
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical class O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- PONXTPCRRASWKW-UHFFFAOYSA-N 1,2-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1C(N)C(N)C1=CC=CC=C1 PONXTPCRRASWKW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000069444 Tetrameres Species 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 125000002355 alkine group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 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
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 125000002734 organomagnesium group Chemical group 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl 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
- 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- UYCAUPASBSROMS-UHFFFAOYSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)F UYCAUPASBSROMS-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
Definitions
- the present document relates to improvements in the field chemistry.
- it relates to a method for preparing diorganozinc compounds.
- R is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 4 -C 30 alkylsilylalkyl, C9-C 30 (alkyl)(aryl)silylalkyl, C 1 9-C30 arylsilylalkyl, C 4 -C 30 (alkyl)(heteroaryl)silylalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 - C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20
- X is chosen from -OR 1 , -SR 1 , Cl, Br, C 2 -C 20 alkylcarboxylate, C 2 -Ci 2 heteroarylcarboxylate, and C 6 -C 20 arylcarboxylate, and when X is Cl or Br, a compound of formula (VI) is further added;
- R is as previously defined
- M is Na or K
- M 1 is Mg
- M 2 is Li, or Na
- T is F, Cl, Br, I, OSO 2 R, OR, CN, or OC(O)R;
- R 1 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a C1-C12 heterocyclyl, or
- R 6 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, C]-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl,
- Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO 2 , - SH, -OR,- -SR, Ci-C 6 alkoxy, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 6 aminoalkyl, C 6 -C 20 aralkyl, C 6 -Ci 2 aryl, C 3 -C 8 cycloalkyl, Ci-Ci 2 heteroaryl, Ci-C] 2 heterocyclyl, C 2 -C 20 carboxylic acid ester, C 3 -C 20 carboxylic acid amide, Ci-C 6 hydroxyalkyl, C 2 -C 3 cyclic acetal, Ci-Ci 2 acetal, Ci-C t2 acyclic orthoester, C 4 -C 6
- R 2 and R 3 are the same or different and they are each Ci-C 20 alkyl, Ci- C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl, C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 4 -C 30 alkylsilylalkyl, C 9 -C 30 (alkyi ⁇ aryl)silylalkyl, Ci 9 -C 30 arylsilylalkyl, C 4 -C 30
- alkyl)(heteroaryl)silylalkyl C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 -Ci 2 cycloalkyl, C]-C] 2 heteroaryl, or Ci-Ci 2 heterocyclyl,
- X is chosen from -OR 1 , -SR 1 , Cl, Br, C 2 -C 20 alkylcarboxylate, C 2 -C] 2 heteroarylcarboxylate, and C 6 -C 20 arylcarboxylate and when X is Cl or Br, a compound of formula (VI) is further added;
- R 2 and R 3 are as previously defined;
- M is Na or K
- M 1 is Mg
- M 2 is Li, or Na
- T is F, Cl, Br, I, OSO 2 R 2 , OR 2 CN, or OC(O)R 2 ;
- R 1 is a Ci-C 20 alkyl, C-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl, or
- R 6 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl,
- Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO 2 , - SH, -OR, -SR, Ci-C 6 alkoxy, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CpC 6 aminoalkyl, C 6 -C 20 aralkyl, C 6 -Ci 2 aryl, C 3 -C 8 cycloalkyl, Ci-Ci 2 heteroaryl, Ci-Ci 2 heterocyclyl, C 2 -C 20 carboxylic acid ester, C 3 -C 20 carboxylic acid amide, Ci-C 6 hydroxyalkyl, C 2 -C 3 cyclic acetal, Ci-Ci 2 acetal, Cj-Ci 2 acyclic orthoester, C 4 -C 6 cycl
- R 2 and R 3 are the same or different and they are each a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl, C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 4 -C 30 alkylsilylalkyl, C 9 -C 30 (alkyl)(aiy l)sily lalkyl, C] 9 -C 30 arylsilylalkyl, C 4 -C 30
- alkyl)(heteroaryl)silylalkyl C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 -Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl,
- X is chosen from -OR 1 , -SR 1 , Cl, Br, C 2 -C 20 alkylcarboxylate, C 2 -Ci 2 heteroarylcarboxylate, and C 6 -C 20 arylcarboxylate ;
- R 2 and R 3 are as previously defined;
- M 1 is Mg
- M is Na or K
- T is F, Cl, Br, I, OSO 2 R 2 , OR, CN, or OC(O)R 2 ;
- R 1 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl; and
- R 6 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 20 alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 20 alkylaminoalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 -C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6 -Ci 2 aryl, C 2 -C 20 carboxylic acid ester, Ci-C 20 carboxylic acid amide, C 3 - Ci 2 cycloalkyl, Ci-Ci 2 heteroaryl, or a Ci-Ci 2 heterocyclyl, each of the alkyl, haloalkyl, hydroxyalkyl, thioal
- Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO 2 , - SH, -OR, -SR, Ci-C 6 alkoxy, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, Ci-C 6 aminoalkyl, C 6 -C 20 aralkyl, C 6 -Ci 2 aryl, C 3 -C 8 cycloalkyl, Ci-Ci 2 heteroaryl, Ci-Ci 2 heterocyclyl, C 2 -C 20 carboxylic acid ester, C 3 -C 20 carboxylic acid amide, Ci-C 6 hydroxyalkyl, C 2 -Ci cyclic acetal, C1-C12 acetal, Ci-Ci 2 acyclic orthoester, Gj-C 6 cyclic ortho
- R 1 is a Ci-C 20 alkyl, Ci-C 20 haloalkyl C 2 -C 20 hydroxyalkyl, C 2 -C 20 thioalkyl, C 2 -C 20 aminoalkyl, C 2 -C 2 O alkoxyalkyl , C 2 -C 20 alkylthioalkyl, C 2 -C 2O alkylaminoalkyl, C 4 -C 30 alkylsilylalkyl, C 9 -C 30 (alkyl)(aryl)silylalkyl, Ci 9 -C 30 arylsilylalkyl, C 4 -C 30 (alkyl)(heteroaryl)silylalkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 2 - C 20 acyl, C 6 -C 20 alkylaryl, C 6 -C 20 arylalkyl, C 6
- the two R 1 groups are linked together so as to form a 5 to 8 membered ring;
- X is Cl or Br
- M is Na or K
- R 1 is as previously defined.
- glyme-type solvent can refer to various solvents.
- a glyme-type solvent can be one of formula R 4 O(CH 2 CH 2 O) n R 5 in which n is 1, 2, or 3, R 4 and R 5 are the same or different and they each represent a Ci-C 4 alkyl.
- alkyl refers to a straight or branched alkyl.
- aryl refers to a cyclic or polycyclic aromatic ring.
- heteroaryl refers to an aromatic cyclic or fused polycyclic ring system having at least one heteroatom selected from the group consisting of N, O, and S.
- the heteroaryl group can be furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
- heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring having an at least one hetero atom (such as nitrogen, oxygen or sulfur).
- this term can include all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
- exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.
- cycloalkyl refers to a hydrocarbon ring which may contain or not double bonds.
- suitable protecting group refers to any suitable protecting group for a given group and described by Wuts, Peter G. M., Greene Theodora W. in Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 4 th edition, December 2006, which is hereby incorporated by reference in its entirety.
- the given group can be the hydroxy group of an hydroxyalkyl, the thiol group of a thioalkyl, the amino group of an aminoalkyl, the alkyne group of an alkynyl etc.
- Suitable protecting groups for an hydroxy group can be, for example, silyls (such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)).
- silyls such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)
- the reaction can be carried out in an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof.
- organic solvent can be chosen from glyme-type solvents.
- Another organic solvent can be further added to the organic solvent.
- the other organic solvent being chosen from Ci -Qo hydrocarbons for example toluene, benzene, hexanes, pentane, and heptane.
- the compound of formula (II) can be reacted with the compounds of formulas (Ilia) (HIb), (IIIc), (IUd), (HIe), (HIf), (HIg), (HIh), (HIi), (IIIj) by preparing a composition comprising the compound of formula (II) and the organic solvent, by adding the at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (Hie), (HIf), (HIg), (HIh), (HIi) and (IIIj) to the composition so as to obtain a mixture, and by agitating the mixture.
- the same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
- the compound of formula (II) can also be reacted with at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (IHe), (HIf), (HIg), (HIh), (HIi), and (IIIj) by preparing a composition comprising the compound of formula (II) and the organic solvent, and by adding the at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (HIe), (HIf), (HIg), (HIh), (HIi), and (IIIj) dissolved in the organic solvent to the composition so as to obtain a mixture, and by agitating the mixture.
- the same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
- a precipitate comprising at least one compound chosen from M 1 X 2 , M 1 XT, M 2 X 2 , and M 2 XT can be formed.
- a liquid phase comprising the compound of formula (I) can be at least partially separated from the precipitate.
- the mixture so-obtained can be centrifuged or filtered so as to separate the precipitate from the liquid phase comprising the compound of formula (I) or (Ia).
- a precipitate comprising a compound of formula TM 1 OR 1 can be formed.
- the mixture so-obtained can be centrifuged or filtered so as to separate the precipitate from a liquid phase comprising the compound of formula (Ia).
- the compound of formula (II) can be reacted with at least one compound chosen from compounds of formulas (Ilia) (HIb), (IHc), (IHd), (HIe), (Illf), (IUg), (IHh), CIIIi), and (IHj) at a temperature of about -20 °C to about 35 0 C or a temperature of about 0 °C.
- the reaction can be carried out at a temperature of about 0° C over a period of time of at least 5 minutes and then a heterogeneous solution so obtained can be allowed to stir at room temperature for a period of at least 5 minutes.
- the same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
- R, R 2 or R 3 can be chosen from a Ci-Ci 2 alkyl, C 8 -Ci 2 arylalkyl, C 6 -Ci 0 aryl, C 4 -C 30 alkylsilylhydroxyalkyl and C 3 -C 6 cycloalkyl.
- R, R 2 or R 3 is chosen from a C 2 -Ci 0 alkyl, C 8 -Ci 2 arylalkyl, benzyl, phenylethyl, phenyl, and C 5 -C 6 cycloalkyl.
- X can be -OR 1 in which R 1 is a Ci-Cj 2 alkyl, C 2 -Ci 2 haloalkyl, C 3 -Ci 2 alkoxyalkyl, C 4 -Ci 2 alkylaminoalkyl, or C 2 -Ci 2 acyl.
- R 1 is RO(CH 2 CH 2 O) n CH 2 CH 2 - in which R is as previously defined and n is 1 , 2 or 3.
- X can be -OR 1 in which R 1 is CH 3 -, «-C 5 Hn, (CH 3 ) 2 CH-, CH 3 C(O)-, PhC(O)-, CF 3 CH 2 -, CH 3 OCH 2 CH 2 -, CH 3 OCH 2 CH 2 OCH 2 CH 2 -, or (CH 3 ) 2 NCH 2 CH 2 -.
- X can be -OR 1 in which R 1 is -CH 3 , H-C 5 H n , CH 3 C(O)-, PhC(O)-, CF 3 CH 2 -, CH 3 OCH 2 CH 2 -, CH 3 OCH 2 CH 2 OCH 2 CH 2 -, or (CH 3 ) 2 NCH 2 CH 2 -.
- X can also be is acetylacetonate.
- the compound of formula (II) can also be Zn(OCH 2 CH 2 O).
- R can be, for example, chosen from a C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C 20 alkylaryl, and C 6 -Ci 2 aryl
- X can be - OMe
- the compound of formula (II) and at least one compound of formula (Ilia), (IHb) or (IIIc) can be reacted together in the presence of NaOMe.
- R can be for example phenyl
- X can be -OMe
- the compound of formula (II) and the at least one compound of formula (Ilia), (HIb) or (IIIc) can be reacted together in the presence of NaOMe.
- the compound of formula (II) can be reacted with a compound of formula (Ilia) in which T is Br or Cl.
- the method for preparing a compound of formula (I) or (Ia) can further comprise carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence or in the absence of a metal.
- the method can also further comprise carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence of a metal and a ligand.
- the metal can be Cu, Ti, Ni, or Zr.
- the nucleophilic addition can be a catalytic enantioselective addition.
- the ligand can be a chiral ligand chosen from Me-DuPHOS(O) morpholino isoborneol (MIB), dimethylaminoisoborneol (DAIB), other amino alcohol based ligands Josiphos, binap, bis(phosphine), taddol, bis(oxazoline), phosphoramidites, phosphites, diamines, PHOX, Binap(O), Binaphtol, and peptide based ligands.
- the nucleophilic addition can be carried out on an imine, an aldehyde, a ketone, or a ⁇ -nitroalkene of the organic substrate.
- the nucleophilic addition can also be a 1-4 addition carried out on an ⁇ , ⁇ -unsaturatedaldehyde or an ⁇ , ⁇ -unsaturatedketone.
- the method for preparing a compound of formula (I) or (Ia) can further comprise carrying out a chemical reaction chosen from an oxidation of a diorganozinc into an alcohol, nucleophilic allylic substitution (S N 2'), a transition metal catalyzed cross-coupling (for example nickel catalyzed cross-coupling or palladium catalyzed cross-coupling), a nucleophilic substitution (for example S N 2 on a ketal), an acylation, an anhydride opening, a carbozincation of an alkene or an alkyne, an allylzincation of alkenylmetal/metalla-aza-claisen, preparation of organozinc or organozinc halides, a cyclopropanation and an epoxidation, by using the compound of formula (I) or (Ia).
- a chemical reaction chosen from an oxidation of a diorganozinc into an alcohol, nucleophilic allylic substitution (S N 2
- a compound of formula (II) can be reacted with a compound of formula (V) in the presence of an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof.
- the organic solvent can be chosen from glyme-type solvents.
- Another organic solvent can further be added to the organic solvent.
- the other organic solvent can be chosen from C 1 -CiO hydrocarbons such as toluene, benzene, hexanes, pentane, and heptane.
- M can be Na and X can be Cl.
- the compounds of formulas (V) and (VI) can be the same.
- both can represent NaOR or KOR in which R is a Ci-C] 0 alkyl.
- Figure 1 is a picture taken during the preparation of Et 2 Zn, wherein (A) represents Zn(OMe) 2 in diethylether, (B) represents a mixture of Zn(OMe) 2 in diethylether into which EtMgCl in diethylether has been added, and (C) represents the mixture shown in (B) after centrifugation, the liquid phase comprising Et 2 Zn and diethylether and the solid phase or precipitate comprising at least one magnesium salt chosen from Mg(OMe) 2 , MgCl(OMe), MgCl 2 , and mixtures thereof.
- Zn(OMe) 2 was not so far commercially available, it can be prepared from Et 2 Zn and MeOH. [ ⁇ x] To bridge this experimental gap, an alternate convenient protocol was developed to generate this salt in situ (Equation 4). The latter was formed from ZnCl 2 and NaOMe (or KOMe). The resulting salt mixture can be used as a surrogate to pure Zn(OMe) 2 and is suitable for the diorganozinc preparation. Et 7 O
- EtZnPh was generated from EtMgBr (1.5 equiv), PhMgBr (1.45 equiv), ZnCl 2 (1.5 equiv) and 1,4-dioxane (10.5 equiv) (see reference
- Mg salts(s) refers to a precipitate that comprises at least one magnesium salt chosen from Mg(OMe) 2 , MgX(OMe), MgX 2 , and mixtures thereof, wherein X is Cl, or Br in accordance with the type of Grignard reagent used i.e. chlorinated or brominated.
- Typical experimental procedure R ⁇ Zn synthesis from Zn(OMe) 2 and RMgCl: To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with Zn(OMe) 2 (637 mg, 5 mmol) was added anhydrous Et 2 O (5 mL) at room temperature. The heterogeneous solution was stirred for 5-15 min and cooled to 0 0 C for another 5-15 min. RMgCl 2M in Et 2 O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 °C, and the heterogeneous solution was allowed to stir at room temperature for 1 h.
- the heterogeneous solution was stirred for 20 min and cooled to 0 0 C for another 5-15 min.
- RMgCl 2M in Et 2 O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 0 C, and the heterogeneous solution was allowed to stir at room temperature for 2 h.
- the mixture was then centrifuged for 5-15 min (or filtered) and the R 2 Zn solution (-0.5 M) was gently transferred via cannula into an empty flame- dried flask purged with argon (or added to a reaction mixture via syringe).
- Typical experimental procedure with Zn(OMe) 2 , NaOMe and RMgBr To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with Zn(OMe) 2 (637 mg, 5 mmol) and NaOMe (650 mg, 12 mmol) was added anhydrous Et 2 O (5 mL) at room temperature. The heterogeneous solution was stirred for 5-15 min and cooled to 0 °C for another 5-15 min. RMgBr 2M in Et 2 O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 0 C, and the heterogeneous solution was allowed to stir at room temperature for 2 h.
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Abstract
There are provided methods for preparing the diorganozmc compounds of formula R2Zn (I or Ia), where R is a defined organic radical, and the two R groups can be the same or different The starting material is the zinc compound ZnX2 (II) or R2ZnX (IIa), where X is a defined anion and R2 is a defined organic radical. The zinc reagent of type II is combined with a Grignard reagent and also, when X is Cl or Br, with an alkali metal reagent (VI) to form the diorganozinc product (I or Ia). Also provided are methods for preparing the zinc alcoholates of formula Zn(OR1)2 by reaction of ZnX2, where X = Cl or Br, with an alkali metal reagent of the formula MOR1, where M = Na or K, and where R1 is a defined organic radical.
Description
METHODS FOR PREPARING DIQRGANOZINC
COMPOUNDS TECHNICAL FIELD
[0001] The present document relates to improvements in the field chemistry. In particular, it relates to a method for preparing diorganozinc compounds.
BACKGROUND OF THE INVENTION
[0002] It is therefore an object of the present invention to provide a support which would overcome the drawbacks of the prior art.
[0003] Finding the right balance between reactivity and selectivity is one of the greatest scientific challenges in modern chemistry. In this context, diorganozinc reagents have proven effective in asymmetric catalysis. [l] Although, this family of organometallic reagents has been known for years, the synthesis of functionalized diorganozinc compounds has, only recently, made some significant progress, beginning with the seminal work of Knochel and co-workers.^111 However, these functionalized diorganozinc reagents are widely underused in asymmetric catalysis, especially in non-academic laboratories. One explanation for this observation is mainly that current methods for preparing them (Equations 1 to 3) are somewhat troublesome. One must deal with (1) the potential hazards caused by the handling and distillation of highly pyrophoric chemicals and/or with (2) the presence of byproducts, which are sometimes in stoichiometric amount and incompatible with catalytic reactions.11111 Depending on the synthetic method used, the main byproducts are either salts,[lv] residual organometallic species such as boranes,[v] or simply an excess of reagent. [vi] Even if some diorganozinc compounds can be purified through simple distillation or sublimation, the approach remains tedious and limited to volatile and low functionalized compounds.
R-Metal + ZnX2 - R2Zn + Metal-X (1)
R1-Metal + ZnR2 2 R1 2Zn + Metal-R2 (2)
R1-X + R2 2Zn R1 2Zn + R2-χ (3)
SUMMARY OF THE INVENTION
[0004] According to one aspect, there is provided a method for preparing a compound of formula (I):
R2Zn (I)
wherein
R is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyl)(aryl)silylalkyl, C19-C30 arylsilylalkyl, C4-C30 (alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2- C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, CI-CJ2 heteroaryl, or a Ci-Ci2 heterocyclyl,
the method comprising reacting a compound of formula (II) with at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc):
ZnX2 (II)
RM1T (Ilia)
R2M1 (HIb)
RM2 (IIIc)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-Ci2 heteroarylcarboxylate, and C6-C20 arylcarboxylate, and when X is Cl or Br, a compound of formula (VI) is further added;
R is as previously defined;
M is Na or K;
M1 is Mg;
M2 is Li, or Na;
T is F, Cl, Br, I, OSO2R, OR, CN, or OC(O)R;
R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a C1-C12 heterocyclyl, or
the two R1 groups are linked together so as to form a 5 to 8 membered ring; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, C]-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryi)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent which is compatible with a diorganozinc compound. Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, -
SH, -OR,- -SR, Ci-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, CrC6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-C]2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ct2 acyclic orthoester, C4-C6 cyclic orthoester, Ci-Ci2 sulfone, Ci-Cj2 sulfoxide, C2-C)2 carbamate, C2-Ci2 urea, C2- Ci2 sulfonamide, C2-Cj2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, C2-Ci2 hydroxamic acid ester, and a suitable protecting group.
[0005] According to another aspect, there is provided a method for preparing a compound of formula (Ia):
R2ZnR3 (Ia)
wherein
R2 and R3 are the same or different and they are each Ci-C20 alkyl, Ci- C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyiχaryl)silylalkyl, Ci9-C30 arylsilylalkyl, C4-C30
(alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, C]-C]2 heteroaryl, or Ci-Ci2 heterocyclyl,
the method comprising reacting a compound of formula (II) with at least one compound chosen from compounds of formulas (HId), (HIe), and (IHf), and a least compound chosen from compounds of formulas (HIg), (HIh), and (HIi), or with a compound of formula (IIIj):
ZnX2 (II)
R2M1T (Hid)
(R2)2M' (HIe)
CIHf)
R3M1T (IUg)
(R^2M1 (HIh)
R3M2 CIHi)
R2M1R3 CIIIj)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-C]2 heteroarylcarboxylate, and C6-C20 arylcarboxylate and when X is Cl or Br, a compound of formula (VI) is further added;
R2 and R3 are as previously defined;
M is Na or K;
M1 is Mg;
M2 is Li, or Na;
T is F, Cl, Br, I, OSO2R2, OR2 CN, or OC(O)R2;
R1 is a Ci-C20 alkyl, C-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl, or
the two R1 groups are linked together so as to form a 5 to 8 membered ring; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20
alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent which is compatible with a diorganozinc compound. Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, - SH, -OR, -SR, Ci-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, CpC6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-Ci2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Cj-Ci2 acyclic orthoester, C4-C6 cyclic orthoester, Ci-Ci2 sulfone, Ci-Cj2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2- Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, C2-Ci2 hydroxamic acid ester, and a suitable protecting group.
[0006] According to another aspect, there is provided a method for preparing a compound of formula (Ia):
R2ZnR3 (Ia)
wherein
R2 and R3 are the same or different and they are each a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyl)(aiy l)sily lalkyl, C]9-C30 arylsilylalkyl, C4-C30
(alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20
alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
the method comprising reacting a compound of formula (Ha) with a compound of formula (IHg), and a compound of formula (VI):
R2ZnX (Ha)
R3M1T (HIg)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-Ci2 heteroarylcarboxylate, and C6-C20 arylcarboxylate ;
R2 and R3 are as previously defined;
M1 is Mg;
M is Na or K;
T is F, Cl, Br, I, OSO2R2, OR, CN, or OC(O)R2;
R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3- Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent which is compatible with a diorganozinc compound. Such a substituent can be chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, - SH, -OR, -SR, Ci-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-Ci2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-Ci cyclic acetal, C1-C12 acetal, Ci-Ci2 acyclic orthoester, Gj-C6 cyclic orthoester, Ci-Cj2 sulfone, Ci-Ci2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2- Cj2 sulfonamide, C2-Cj2 sulfoxamide, C2-Ci2 phosphonate, C2-Cj2 phosphinoyl, C2-Cj2 hydroxamic acid ester, and a suitable protecting group.
[0007] It was found that such methods can be applied to a wide scope of reactions. It was also found that such a method is an efficient, safe and general method for preparing diorganozinc reagents while eliminating susbtantially all byproducts. Advantages such as the high reactivity of certain intermediates, for example organomagnesium reagents, their readily commercial availability and their ease of preparation and handling, permits to easily employ them as main precursors for diorganozinc reagents synthesis. These two methods can be used under the same reaction conditions.
[0008] According to another aspect, there is provided a method for preparing a compound of formula (IV):
Zn(OR')2 (IV) wherein R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C2O alkoxyalkyl , C2-C20 alkylthioalkyl, C2-C2O alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyl)(aryl)silylalkyl, Ci9-C30 arylsilylalkyl, C4-C30 (alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2- C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-C!2 aryl, C2-C20 carboxylic acid ester,
C1-C20 carboxylic acid amide, C3-C12 cycloalkyl, C1-C12 heteroaryl, or a Ci-Ci2 heterocyclyl, or
the two R1 groups are linked together so as to form a 5 to 8 membered ring;
each of the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, - OH, -CN, -NO2, -SH, -OR, -SR, C-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-C]2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ci2 acyclic orthoester, C4-C6 cyclic orthoester, C1-C12 sulfone, Ci-Cj2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2-Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, C2-Ci2hydroxamic acid ester, and a suitable protecting group,
the method comprising reacting a compound of formula (II) with a compound of formula (V):
ZnX2 (II)
MOR1 (V)
wherein
X is Cl or Br;
M is Na or K; and
R1 is as previously defined.
[0009] The expression "glyme-type solvent" as used herein can refer to various solvents. For example, a glyme-type solvent can be one of formula
R4O(CH2CH2O)nR5 in which n is 1, 2, or 3, R4 and R5 are the same or different and they each represent a Ci-C4 alkyl.
[0010] The term "alkyl" as used herein refers to a straight or branched alkyl.
[0011] The term "aryl" as used herein refers to a cyclic or polycyclic aromatic ring.
[0012] The term "heteroaryl" as used herein refers to an aromatic cyclic or fused polycyclic ring system having at least one heteroatom selected from the group consisting of N, O, and S. For example, the heteroaryl group can be furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
[0013] The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring having an at least one hetero atom (such as nitrogen, oxygen or sulfur). For example, this term can include all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.
[0014] The term "cycloalkyl" as used herein refers to a hydrocarbon ring which may contain or not double bonds.
[0015] The expression "suitable protecting group" refers to any suitable protecting group for a given group and described by Wuts, Peter G. M., Greene Theodora W. in Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 4th edition, December 2006, which is hereby incorporated by reference in its entirety. For example, the given group can be the hydroxy group of an hydroxyalkyl, the thiol group of a thioalkyl, the amino group of an aminoalkyl, the alkyne group of an alkynyl etc. Suitable protecting groups for an hydroxy group can be, for example,
silyls (such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)).
[0016] When preparing a compound of formula (I) or (Ia) the reaction can be carried out in an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof. Alternatively, the organic solvent can be chosen from glyme-type solvents. Another organic solvent can be further added to the organic solvent. The other organic solvent being chosen from Ci -Qo hydrocarbons for example toluene, benzene, hexanes, pentane, and heptane.
[0017] The compound of formula (II) and the compound(s) of formula(s) (HIa)- (HIi) can be reacted together in the organic solvent and agitated. The same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
[0018] The compound of formula (II) can be reacted with the compounds of formulas (Ilia) (HIb), (IIIc), (IUd), (HIe), (HIf), (HIg), (HIh), (HIi), (IIIj) by preparing a composition comprising the compound of formula (II) and the organic solvent, by adding the at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (Hie), (HIf), (HIg), (HIh), (HIi) and (IIIj) to the composition so as to obtain a mixture, and by agitating the mixture. The same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
[0019] The compound of formula (II) can also be reacted with at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (IHe), (HIf), (HIg), (HIh), (HIi), and (IIIj) by preparing a composition comprising the compound of formula (II) and the organic solvent, and by adding the at least one compound chosen from compounds of formulas (Ilia) (HIb), (IIIc), (Hid), (HIe), (HIf), (HIg), (HIh), (HIi), and (IIIj) dissolved in the organic solvent to the composition so as to obtain a mixture, and by agitating the mixture. The same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
[0020] When preparing a compound of formula (I) or (Ia), a precipitate comprising at least one compound chosen from M1X2, M1XT, M2X2, and M2XT can
be formed. A liquid phase comprising the compound of formula (I) can be at least partially separated from the precipitate. The mixture so-obtained can be centrifuged or filtered so as to separate the precipitate from the liquid phase comprising the compound of formula (I) or (Ia).
[0021] When preparing a compound of formula (Ia), a precipitate comprising a compound of formula TM1OR1 can be formed. The mixture so-obtained can be centrifuged or filtered so as to separate the precipitate from a liquid phase comprising the compound of formula (Ia).
[0022] The compound of formula (II) can be reacted with at least one compound chosen from compounds of formulas (Ilia) (HIb), (IHc), (IHd), (HIe), (Illf), (IUg), (IHh), CIIIi), and (IHj) at a temperature of about -20 °C to about 35 0C or a temperature of about 0 °C. The reaction can be carried out at a temperature of about 0° C over a period of time of at least 5 minutes and then a heterogeneous solution so obtained can be allowed to stir at room temperature for a period of at least 5 minutes. The same can also be applied to compounds of formulas (Ha), (HIg) and (VI).
[0023] For example, R, R2 or R3 can be chosen from a Ci-Ci2 alkyl, C8-Ci2 arylalkyl, C6-Ci0 aryl, C4-C30 alkylsilylhydroxyalkyl and C3-C6 cycloalkyl. Alternatively, R, R2 or R3 is chosen from a C2-Ci0 alkyl, C8-Ci2 arylalkyl, benzyl, phenylethyl, phenyl, and C5-C6 cycloalkyl.
[0024] For example, X can be -OR1 in which R1 is a Ci-Cj2 alkyl, C2-Ci2 haloalkyl, C3-Ci2 alkoxyalkyl, C4-Ci2 alkylaminoalkyl, or C2-Ci2 acyl. Alternatively, X can be -OR1 in which R1 is RO(CH2CH2O)nCH2CH2- in which R is as previously defined and n is 1 , 2 or 3.
[0025] For example, X can be -OR1 in which R1 is CH3-, «-C5Hn, (CH3)2CH-, CH3C(O)-, PhC(O)-, CF3CH2-, CH3OCH2CH2-, CH3OCH2CH2OCH2CH2-, or (CH3)2NCH2CH2-. Alternatively, X can be -OR1 in which R1 is -CH3, H-C5Hn, CH3C(O)-, PhC(O)-, CF3CH2-, CH3OCH2CH2-, CH3OCH2CH2OCH2CH2-, or (CH3)2NCH2CH2-. X can also be is acetylacetonate. The compound of formula (II) can also be Zn(OCH2CH2O).
[0026] When preparing a compound of formula (I) R can be, for example, chosen from a C2-C20 alkenyl, C2-C20 alkynyl, C6-C20 alkylaryl, and C6-Ci2 aryl, X can be - OMe, and wherein the compound of formula (II) and at least one compound of formula (Ilia), (IHb) or (IIIc) can be reacted together in the presence of NaOMe. Alternatively, R can be for example phenyl, X can be -OMe, and wherein the compound of formula (II) and the at least one compound of formula (Ilia), (HIb) or (IIIc) can be reacted together in the presence of NaOMe.
[0027] For example, the compound of formula (II) can be reacted with a compound of formula (Ilia) in which T is Br or Cl.
[0028] The method for preparing a compound of formula (I) or (Ia) can further comprise carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence or in the absence of a metal. The method can also further comprise carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence of a metal and a ligand. For example, the metal can be Cu, Ti, Ni, or Zr. The nucleophilic addition can be a catalytic enantioselective addition. For example, the ligand can be a chiral ligand chosen from Me-DuPHOS(O) morpholino isoborneol (MIB), dimethylaminoisoborneol (DAIB), other amino alcohol based ligands Josiphos, binap, bis(phosphine), taddol, bis(oxazoline), phosphoramidites, phosphites, diamines, PHOX, Binap(O), Binaphtol, and peptide based ligands. The nucleophilic addition can be carried out on an imine, an aldehyde, a ketone, or a β-nitroalkene of the organic substrate. The nucleophilic addition can also be a 1-4 addition carried out on an α,β-unsaturatedaldehyde or an α,β-unsaturatedketone.
[0029] The method for preparing a compound of formula (I) or (Ia) can further comprise carrying out a chemical reaction chosen from an oxidation of a diorganozinc into an alcohol, nucleophilic allylic substitution (SN2'), a transition metal catalyzed cross-coupling (for example nickel catalyzed cross-coupling or palladium catalyzed cross-coupling), a nucleophilic substitution (for example SN2 on a ketal), an acylation, an anhydride opening, a carbozincation of an alkene or an
alkyne, an allylzincation of alkenylmetal/metalla-aza-claisen, preparation of organozinc or organozinc halides, a cyclopropanation and an epoxidation, by using the compound of formula (I) or (Ia).
[0030] When preparing a compound of formula (IV), a compound of formula (II) can be reacted with a compound of formula (V) in the presence of an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof. Alternatively, the organic solvent can be chosen from glyme-type solvents. Another organic solvent can further be added to the organic solvent. The other organic solvent can be chosen from C1-CiO hydrocarbons such as toluene, benzene, hexanes, pentane, and heptane. For example, M can be Na and X can be Cl.
[0031] The compounds of formulas (V) and (VI) can be the same. For example, both can represent NaOR or KOR in which R is a Ci-C]0 alkyl.
[0032] The person skilled in the art would clearly recognize that the processes for preparing compounds of formula (Ia) is similar to the process for preparing compounds of formula (I). In fact, the particular embodiments and examples previously mentioned concerning the process for preparing compounds of formula (I), when possible, can all be applied to the processes for preparing compounds of formula (Ia).
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Further features and advantages will become more readily apparent from the following description of various embodiments as illustrated by way of examples in the appended drawings wherein:
[0034] Figure 1 is a picture taken during the preparation of Et2Zn, wherein (A) represents Zn(OMe)2 in diethylether, (B) represents a mixture of Zn(OMe)2 in diethylether into which EtMgCl in diethylether has been added, and (C) represents the mixture shown in (B) after centrifugation, the liquid phase comprising Et2Zn and
diethylether and the solid phase or precipitate comprising at least one magnesium salt chosen from Mg(OMe)2, MgCl(OMe), MgCl2, and mixtures thereof.
DETAILLED DESCRIPTION OF VARIOUS EMBODIMENTS
[0035] The following examples represent in a non-limitative manner, various embodiments.
[0036] Since the addition of a Grignard reagent on a zinc salt potentially generates several organic, organometallic and inorganic species, some of which are actually in equilibrium with each other[v"] and since it is difficult to accurately dose organometallic and inorganic impurities found in diorganozinc solutions, several tests have been carried out by using the prepared R2Zn solution in the catalytic enantioselective addition to imines.[v'"] This reaction is known to be very sensitive to the presence of salts.
Table 1. Zinc Salts Screening
ZnX2 EtMgCI in Et2O (2 equiv) (3 95 equiv)
Et2O
Et2Zn Mg salt(s) I
Entry X Yield ee
[%][a] [%][b]
1 none[cj >95 O
2 Cl 51 27
3 MeO 95 97
4 CF3CH2O 46 10
6 CH3OCH2CH2O 88 97
7 CH3OCH2CH2OCH2CH2O 65 88
8 (CHs)2NCH2CH2O 78 2
9 Acac 44 55
10 ^C5Hi iO 45 41
11 AcO 94 97
12 BzO 57 27
13 CH2=CHCOO 45 89
14 OCH2CH2O 59 O
15[d] MeO 21 35
16[e] AcO >95 97
17W MeO 90 13
[a] NMR yields determined using an internal standard, [b] Enantiomeric excesses were determined by SFC on chiral stationary phase, [c] No zinc salt was used, [d] 3.95 equiv of EtMgBr in Et2O was used, [e] 4.5 equiv of EtMgCl was used.
[0037] It was observed that the method for preparing diorganozinc is technically simple easy and fast. A simple manual or mechanical stirring of the reaction during the preparation of the organozinc compounds can be made (see Figure 1). Filtration or centrifugation can also be used so as to led to a salt free diorganozinc solution. Although similar results in terms of purity of the diorganozinc formed can be obtained using either technique, each offers certain advantages. While centrifugation is quick and allows the simultaneous treatment of several samples, filtration, on the other hand, allows a better recovering of the solution and works well on a large scale.
[0038] Since Zn(OMe)2 was not so far commercially available, it can be prepared from Et2Zn and MeOH. [ιx] To bridge this experimental gap, an alternate convenient protocol was developed to generate this salt in situ (Equation 4). The latter was formed from ZnCl2 and NaOMe (or KOMe). The resulting salt mixture can be used as a surrogate to pure Zn(OMe)2 and is suitable for the diorganozinc preparation.
Et7O
ZnX2 + NaOMe - — - Zn(OMe)2 + NaX (4)
(1 equiv) (2-2.5 equiv) (1 equiv) (2 equiv)
X = CL Br
[0039] When compared to the addition of neat Et2Zn, the use of Zn(OMe)2, either isolated or generated in situ, produced excellent yields and selectivities (Table 2, entries 1-3). In a similar fashion, the addition of more functionalized zinc salts was just as successful, suggesting that their purity was equally excellent.
Table 2. Catalytic enantioselective addition to imines
Zn(OMe)2 + RMgCI in Et2O
(2 equiv) (3 95 equiv)
Et2O
R2Zn i + Mg salt(s) I
Cu(OTf)2 (10 mol %)
Toluene O 0C1 16 h
Entry R Yield [°/c ][a] ee [%][b]
1 Et 95 98
2 Et[c] 90 98
6 H-Bu 96 96
7 /-Pr 57 95
[a] Isolated yields, [b] Enantiomeric excesses were determined by SFC on chiral stationary phase, [c] Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). [d] Neat Et2Zn was dissolved in Et2O. [e] The reaction was run for 48 h.
[0040] As it can be seen in Schemes 1 and 2, further examples of catalytic enantioselective addition to imines was made. In these two examples the reaction was carried out by preparing and using a mixed diorganozinc (R2ZnR3) and more particularly H-Ci0H21ZnCH2TMS and BnZnMe.
Scheme 1. Catalytic enantioselective addition to imines using mixed diorganozinc
Zn(OMe)2 + π-C10H21MgCI + TMSCH2MgCI (2 equιv) (1 9 equιv) (2 equiv)
Et2O
Cn-C10H21)ZnCH2TMS + Mg salt(s) I Centrifugation
(5 mol %)
47%, 95% e e
Scheme 2. Catalytic enantioselective addition to imines using mixed diorganozinc
Zn(OMe)2 BnMgCI TMSCH2MgCI
(2 equiv) (1 9 equιv) (2 equiv)
Et2O
BnZnCH2TMS + Mg salt(s) ^
[0041] To prove the generality of such a methodology, various enantioselective addition systems were tested: the addition to β-nitroalkenes, to cyclohexenones and to aldehydes. Results obtained for the addition to β-nitroalkenes [x] turned out to be similar to the previous ones (Table 3).
Table 3. Catalytic enantioselective addition to β-nitroalkenes
Zn(OMe)2 + RMgCI m Et2O (2 equiv) (3 95 equiv)
J Et2O R2Zn + Mg salt(s) l
%)
Et2O, -70 °C, 2O h
Entry R Yield [%][a] ee [%] [b]
1 Et 92 94
2 Et[c] 90 95
3 Et[d] 92 95
4 «-CioH2i n.d. n.d.
ΓΛ
5 O O n.d. n.d.
[a] Isolated yields, [b] Enantiomeric excesses were determined by GC on chiral stationary phase, [c] Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). ZnBr2 was also used instead of ZnCl2 and similar results were obtained, [d] Neat Et2Zn was dissolved in Et2O.
[0042] The conjugated catalytic addition to cyclohexenone[xi] also proceeded smoothly with excellent reactivity. As the data indicate in Table 4, the synthesis of dialkylzinc reagents from Zn(OMe)2 tolerated primary, secondary, branched, linear or long chains. Furthermore, functionalities are well tolerated insofar as Grignard reagents themselves are compatible with them.
Table 4. Catalytic enantioselective conjugated addition to cyclohexenone
Zn(OMe)2 ■ RMgCI in Et2O (2 equiv) (3 95 equiv)
Et2O
R2Zn ■ Mg salt(s) I
Centπfugation or filtration
Cu(OTf)2 (2 mol %) Toluene, -30 "C, 20 h
Entry R Yield ee [%] [b]
[a]
[%]
1 Et 89 >98ltJ
2 Et[c] 88 >98[fl
3 Et[d] 86 >98[f!
4 Me n.d. n.d.
6 n-Bu 94 >95
7 /-Bu 95 97
8 c-Hex 94 94
9 "-Ci0H2 I 97 >98[f]
1 0[e] "-Ci0H2I n.d. n.d.
1 1 t-Bu 84, 19[gl 6, 27[g]
12 PhCH2CH2- 97 >98[fl
13 ΓΛ o o n.d. n.d.
[a] Isolated yield, [b] Enantiomeric excesses were determined by SFC on chiral stationary phase or by 13C NMR spectroscopy after derivatization with 1,2-diphenyl ethylenediamine. [c] Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). [d] Neat R2Zn was dissolved in Et2O. [e] Zn(Ci0H2O2 was generated by hydroboration according to reference [3]. [fj The minor enantiomer could not be detected, [g] 1.0 equivalent of styrene has been added.
[0043] Further study of the reactivity of dialkylzinc reagents prepared with the method, reactions catalyzed by chiral amino alcohols have been tested. [X1|] Once again, results of Table 5 showed that the enantioselective addition to aldehydes was very successful.
Table 5. Catalytic enantioselective addition to aldehydes
Zn(OMe)2 RMgCI in Et2O (2 equiv) (3 95 equιv)
Et2O
R2Zn Mg sa lt(s) I on
h
Entry R Yield [%][a] ee [%] [b]
1 Et 93 98
2 Et[β] 95 98
3 Et[d] 96 97
4 "-Ci0H2I 63[c] 97
5 o ΓΛ o n.d. n.d.
[a] Isolated yields, [b] Enantiomeric excesses were determined by SFC on chiral stationary phase, [c] Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). [d] Neat Et2Zn was dissolved in Et2O. [e] The low yield is explained by the formation of the reduction product.
[0044] Moreover, the synthesis of mixed diorganozinc reagents was found to be very simple: two different Grignard reagents can be added to Zn(OMe)2 (entries A-
[0045] A further example of addition to an aldehyde is shown in Scheme 3. In this particular example, a mixed diorganozinc (R2ZnR3) was prepared and used.
Scheme 3. Catalytic enantioselective addition to aldehydes using mixed diorganozinc
Zn(OMe)2 BnMgCI MeMgCI
(2 equιv) (1 9 equiv) (2 equιv)
I Et2θ
BnZnMe + Mg salt(s) I
99% conv , 87% e e
[0046] Some other examples involving arylmagnesium reagents have also been made as shown in Table 6.
Table 6. Modification using brominated Grignard reagents
Zn(OMe)2 RMgBr NaOMe (2 equiv) (3 9 equiv) (4 8 equiv)
Et2O
R2Zn Mg salt(s) I NaBr I
Cent n fug at ion or filtration
Entry R Yield [%][a] ee [%] [b]
1 Et 96 98
2 Et[c] 92 98
3 Ph 90 98
4[d], [e] Ph 98 98
5[d], [f] Ph 63 98
6 TBDMSO(CH2)4 70 98
[a] Isolated yield, [b] Enantiomeric excesses were determined by SFC on chiral stationary phase, [c] EtMgBr (3.3 equiv) was used in combination with NaOBz (0.6 equiv). [d] Mixed diorganozinc was used, [d] EtZnPh was generated from EtMgBr (1.5 equiv) and PhMgBr (1.45 equiv). [e] EtZnPh was generated from Et2Zn (0.75 equiv) and Ph2Zn (0.75 equiv). [fj EtZnPh was generated from EtMgBr (1.5 equiv), PhMgBr (1.45 equiv), ZnCl2 (1.5 equiv) and 1,4-dioxane (10.5 equiv) (see reference
[Xi]).
[0047] Since a slight excess of Zn(OMe)2 can be used in proportion to the Grignard reagent, traces of RZnOMe can still remain in the solution. However, such species are known to generate a stable tetramere, creating little or no interactions with catalytic systems, as illustrated herein. When necessary, the use of an excess of Grignard reagent in combination with an insoluble and slow to react scavenger such as NaOBz, [xιv] will eliminate the presence of organozinc alkoxide (Table 6, entry 2).
[0048] In summary, the low solubility of magnesium salts such as magnesium methoxide has been exploited in order to synthesize diorganozinc reagents dissolved in Et2O without unwanted reaction by-products. It represents an attractive method to access both highly functionalized dialkylzinc and diarylzinc reagents. It also permits to easily prepare diorganozinc compounds. Finally, such a method shows no change in the reactivity of all tested asymmetric catalytic reactions in comparison to purified reagents.
[0049] In Tables 1 to 6 and Schemes 1 to 3 the expression "Mg salts(s)" refers to a precipitate that comprises at least one magnesium salt chosen from Mg(OMe)2, MgX(OMe), MgX2, and mixtures thereof, wherein X is Cl, or Br in accordance with the type of Grignard reagent used i.e. chlorinated or brominated.
Examples
[0050] Typical experimental procedure: R∑Zn synthesis from Zn(OMe)2 and RMgCl: To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with Zn(OMe)2 (637 mg, 5 mmol) was added anhydrous Et2O (5 mL) at room temperature. The heterogeneous solution was stirred for 5-15 min and cooled to 0 0C for another 5-15 min. RMgCl 2M in Et2O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 °C, and the heterogeneous solution was allowed to stir at room temperature for 1 h. The mixture was then centrifuged for 5-15 min (or filtered) and the R2Zn solution (~0.5 M)[xv]'[xvι] was gently transferred via cannula into an empty flame-dried flask purged with argon (or added to a reaction mixture via syringe).
[0051] Typical experimental procedure: R2Zn synthesis from ZnCI2, NaOMe and RMgCl: To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with ZnCl2 (682 mg, 5 mmol) and NaOMe (567 mg, 10.5 mmol) was added anhydrous Et2O (5 mL) at room temperature (exothermic). The heterogeneous solution was stirred for 20 min and cooled to 0 0C for another 5-15 min. RMgCl 2M in Et2O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 0C, and the heterogeneous solution was allowed to stir at room temperature for 2 h. The mixture was then centrifuged for 5-15 min (or filtered) and the R2Zn solution (-0.5 M) was gently transferred via cannula into an empty flame- dried flask purged with argon (or added to a reaction mixture via syringe).
[0052] Typical experimental procedure with Zn(OMe)2, NaOMe and RMgBr: To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with Zn(OMe)2 (637 mg, 5 mmol) and NaOMe (650 mg, 12 mmol) was added anhydrous Et2O (5 mL) at room temperature. The heterogeneous solution was stirred for 5-15 min and cooled to 0 °C for another 5-15 min. RMgBr 2M in Et2O (9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 0C, and the heterogeneous solution was allowed to stir at room temperature for 2 h. The mixture was then centrifuged for 5-15 min (or filtered) and the R2Zn solution (=0.5 M) was gently canulated in an empty flame-dried flask purged with argon (or added to a reaction with a syringe).
[0053] Typical experimental procedure with mixed diorganozinc compounds
(R2ZnR3) : To a test tube (18x100 mm) equipped with a magnetic stirrer (under argon atmosphere) charged with Zn(OMe)2 (637 mg, 5 mmol) was added anhydrous Et2O (5 mL) at room temperature. The heterogeneous solution was stirred for 5-15 min and cooled to 0 0C for another 5-15 min. R2MgCl 2M in Et2O (5.00 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 °C, then R3MgCl 2M in Et2O (4.75 mmol) was added dropwise with vigorous stirring over 5-10 min at 0 °C and the heterogeneous solution was allowed to stir at room temperature for 1 h. The mixture was then centrifuged for 5-15 min (or filtered) and the R2ZnR3 solution (=0.5 M)[xv] was gently transferred via cannula into an empty flame-dried flask purged with argon (or added to a reaction mixture via syringe).
Characterization
[0054] Other than exceptional cases, compounds in Tables 1 to 6 and Scheme 1 were fully characterized (NMR 1H and 13C, IR, mp, [α]o, MS, E. A, etc.). Exceptions are compounds obtained by addition of t-butyl and benzyl (Table 4, entry 1 1 ; Scheme 2 and 3), for which only NMR 1H and GC/SFC data are available. For known compounds, obtained data are consistent with literature values. xv"'xvι". For new compounds (Table 2, entry 4; Scheme 1; Table 4, entry 9; Table 5, entry 4 and Table 6, entry 6) characterization values are consistent with proposed structures and are reported hereafter.
[0055] i'rP-diphenyl-Λr-[(lS)-l-phenylundecyl]phosphinic amide: mp 95-96 0C; R1 0.55 (10 : 90 hexane : EtOAc); [α]D 20 -6.0 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J= 6.9 Hz, 2H), 1.05-1.37 (m, 8H), 1.75-1.87 (m, IH), 1.92- 2.04 (m, IH), 3.35 (dd, J= 9.6, 6.5 Hz, OH), 4.16 (qd, J= 9.6, 6.5 Hz, IH), 7.17 (dd, J = 7.0, 1.3 Hz, IH), 7.20-7.35 (m, 3H), 7.37-7.51 (m, 2H), 7.76 (ddd, J = 11.9, 8.2, 1.1 Hz, IH), 7.87 (ddd, J = 11.8, 8.1, 1.2 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 13.7, 22.3, 25.7, 28.9, 29.0, 29.0, 29.2 (2C), 31.5, 39.4 (d, Jc-P = 3.8 Hz), 55.5, 126.1, 126.6, 127.8 (d, Jc-P = 12.7 Hz), 128.0 (d, Jc-P = 12.5 Hz), 128.1, 131.2 (d, Jc-P = 2.7 Hz), 131.4 (d, Jc-P = 2.7 Hz), 131.5 (d, Jc-P = 9.8 Hz), 132.2 (d, Jc-P = 9.8 Hz), 131.8 (d, Jc-F = 121.9 Hz), 133.7 (d, Jc-P = 120.7 Hz), 143.6 (d, Jc-P = 6 Hz); 31P NMR (162 MHz, CDCl3) δ 22.78; HRMS m/z (APCI+) calcd for C29H39N OP [M+H]+: 448.27693; found: 448.2770; IR (neat) 3147, 2923, 2853, 1457, 1438, 1197, 1181, 1108, 1068, 932, 750, 720, 693, 605 cm"1.
[0056] (35)-3-decyIcyclohexanone: Rf 0.51 (90 : 10 «-hexane : EtOAc); [α]D 20 - 12.1 (c 1.08, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 6.9 Hz, 3H), 1.13- 1.35 (m, 19H), 1.52-1.65 (m, IH), 1.71 (s, IH), 1.80-1.89 (m, IH), 1.90-2.04 (m, 2H), 2.14-2.24 (m, IH), 2.28 (dd, J = 10.4, 7.0 Hz, IH), 2.33-2.40 (m, IH); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.7, 25.4, 26.7, 29.4, 29.7 (2C), 29.7, 29.8, 31.4, 32.0, 36.7, 39.2, 41.5, 48.3, 21 1.7; HRMS m/z (APCI+) calcd for C6H31O [M+H]+: 239.23694; found: 239.23696; IR (neat) 2922, 2852, 1714, 1465, 1345, 1313, 1224, 815, 722, 630 cm"1.
[0057] (lS)-l-(2-naphthyl)-l-undecanol: mp 53-54 0C; R1 0.35 (20 : 80 EtOAc : hexane); [α]D 20 -23.0 (c 1.08 CHCl3); 1H NMR (400 Hz, CDCl3) δ 0.96 (t, J= 6.8 Hz, 3H), 1.32 (s, 15H), 1.45 (d, J = 8.7 Hz, IH), 1.97-1.74 (m, 2H), 2.46 (s, IH), 4.81 (t, J = 6.6 Hz, IH), 7.57-7.46 (m, 3H), 7.77 (s, IH), 7.92-7.81 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 14.3, 22.9, 26.0, 29.5, 29.7 (2C), 29.8 (2C), 32.1, 39.1, 74.9, 124.3, 124.8, 125.9, 126.2, 127.8, 128.1, 128.3, 133.1, 133.4, 142.5.; HRMS m/z (APCI+) calcd for C2,H30NaO [M+Na]+: 321.21888; found: 321.21787; IR (neat) 3273, 3054, 2919, 2850, 1507, 1465, 1313, 1065, 1031, 896, 860, 826, 748 cm-1
[0058] (IS)- 5-{[tert-butyl(dimethyl)siIyl]oxy}-l-(2-naphthyl)-l-pentanol : Rf
0.25 (20 : 80 EtOAc : hexane); [α]D 20 -19.5 (c 1.04 CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.29-1.40 (m, IH), 1.42-1.51 (m, IH), 1.55 (qn, J = 6.9 Hz 2H), 1.75-1.94 (m, 2H), 2.17 (d, J = 3.1 Hz, IH), 3.58 (t, J = 6.4 Hz, 2H), 4.81 (td, J= 6.7, 2.9 Hz, IH), 7.40-7.51 (m, 3H), 7.75 (s, IH), 7.77-7.87 (m, 3H); 13C NMR (100 MHz, CDCl3) δ -5.1, 18.5, 22.3, 26.2, 32.8, 38.9, 63.3, 74.9, 124.3, 124.8, 125.9, 126.3, 127.9, 128.1, 128.4, 133.2, 133.5, 142.4; HRMS m/z (APCI+) calcd for C2IH32NaO2Si [M+Na]+: 367.20638; found: 367.20512; IR (neat) 3351, 3055, 2928, 2856, 1602, 1508, 1471, 1462, 1387, 1360, 1254, 1096, 835, 775, 746, 662 cm"1.
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[X1V] In most cases, CH3CO2Na and CF3CO2Na also afford good results
[xv] For a more precise concentration A Krasovskiy, P Knochel, Synthesis, 2006, 890-891
[xvl] The volume of the recovered solution is dependent on the nature of the Gπgnard reagent For example, 6 mL of Et2Zn solution (0 5M) was obtained with EtMgCl
[XU1] For more details about the characterization data, see A Cόte, A B Charette, J Am Chem Soc 2008, /50, 2771-2773
[XV1"| a) A A Boezio, J Pytkowicz, A Cδte, A B Charette, J Am Chem Soc 2003, /25, 14260- 14261 , b) T Suzuki, T Shibata, K Soai, J Chem Soc , Perkin Trans 1 1997, 2757-2760, c) H - L Zhang, X -M Zhang, L -Z Gong, A -Q Mi, X Cui, Y -Z Jiang, M C K Choi, A S C Chan, Org Lett 2002, 4, 1399-1402, d) B -M Park, S Mun, J Yun, Adv Synth Catal 2006, 348, 1029-1032, e) X -M Zhang, H -L Zhang, W -Q Lin, L -Z Gong, A -Q Mi, X Cui, Y -Z Jiang, K -B Yu, J Org Chem 2003, 68, 4322-4329, f) A Alexakis, C Benhaim, S Rosset, M Wummzn, J Am Chem Soc 2002, 124, 5262-5263, g) M -C Wang, C -L Xu, F Cheng, X Ding, Tetrahedron 2006, 62, 12220-12226, h) J -N Desrosiers, A Cδte, A A Boezio, A B Charette, Org Synth 2006, 83, 5-17, i) K Soai, T Hatanaka, T Miyazawa, Chem Commun 1992, 1097, j) H -L Zhang, X M Zhang, L Z Gong, A Q Mi, X Cui, Y Z Jiang, M C K Choi, A S C Chan, Org Lett 2002, 4, 1399, k) P G Andersson, D Guijarro, D Tanner, J Org Chem 1997, 62, 7364, I) P Pinho, P G Andersson, Tetrahedron 2001, 57, 1615, m) T Suzuki, Y Hirokawa, K Ohtake, T Shibata, K Soai, Tetrahedron Asymmetry 1997, 8, 4033, n) D Guijarro, P Pinho, P G Andersson, J Org Chem 1998, 63, 2530, o) T Suzuki, T Shibata, K Soai, J Chem Soc , Perkin Trans 1 1997, 2757, p) X M Zhang, L H Gong, A Q Mi, X Cui, Y H Jiang, M C K Choi, A S C Chan, Tetrahedron Lett 2001, 42, 6369-6372 q) I Sato, R Kodaka, K Soai, J Chem Soc , Perkin Trans 1 2001, 2912, r) C Jimeno, A Vidal- Ferran, A Moyano, M A Peπcas, A Riera, Tetrahedron Lett 1999, 40, 777, s) K Soai, T Suzuki, T Shono, Chem Commun 1994, 317, t) I Sato, R Kodaka, K Soai, J Chem Soc , Perkin Trans 1 2001, 2912, u) W Buchowiecki, Z Grosman-Zjawiona, J Zjawiony, Tetrahedron Lett 1985, 26, 1245- 1248, v) S Degrado, H Mizutam, A H Hoveyda, J Am Chem Soc 2001, 123, 755-756, w) J B Tuttle, S G Ouellet, D W C MacMillan, J Am Chem Soc 2006, 128, 12662-12663, x) E L Stangeland, T Sammakia, Tetrahedron 1997, 53, 16503-16510, y) Q -L Zhou, A Pfaltz, Tetrahedron 1994, 50, 4467-4478, z) E J Corey, R Naef, F J Hannon. J Λw Chem Soc 1986, 108, 71 14-71 16, aa) N J A Martin, B List, J Am Chem Soc 2006, 128, 13368-13369, ab) M Kanai, Y Nakagawa, K Tomioka, Tetrahedron 1999, 55, 3843-3854, ac) M J Totleben, D P Curran, P Wipf. J Org Chem 1992, 57, 1740- 1744, (d) J -Y Liu, Y -J Jang, W -W Lm, J -T Liu, C -F Yao, J Org Chem 2003, 65, 4030- 4038, ae) P Jones, C K Reddy, P Knochel, Tetrahedron 1998, 54, 1471 - 1490, af) P Wipf, W Xu, J H Smitrovich, R Lehmann, L M Venanzi, Tetrahedron 1994, 50, 1935- 1954, ag) R D Rieke, W R Klein, T -C Wu, J Org Chem 1993, 58, 2492-2500, ah) C R Graves, K A
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Claims
1. A method for preparing a compound of formula (I):
R2Zn (I)
wherein
R is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, Cg-C30 (alkyl)(aryl)silylalkyl, C 19-C30 arylsilylalkyl, C4-C30 (alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl,
C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
said method comprising reacting a compound of formula (II) with at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc):
ZnX2 (II)
RM1T (Ilia)
R2M1 (UIb)
RM2 (IIIc)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-Ci2 heteroarylcarboxylate, and C6-C20 arylcarboxylate, and when X is Cl or Br, a compound of formula (VI) is further added;
R is as previously defined;
M is Na or K;
M1 is Mg;
M2 is Li, or Na;
T is F, Cl, Br, I, OSO2R, CN, OR or OC(O)R;
R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, C]-C20 carboxylic acid amide, C3-Cj2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl, or
said R1 are linked together so as to form a 5 to 8 membered ring; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, - SH, -OR, -SR, Ci-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C,-
C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-C]2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-C]2
acetal, C1-Cj2 acyclic orthoester, C4-C6 cyclic orthoester, C1-C12 sulfone, Ci- Ci2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2-Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, C2-Cj2 hydroxamic acid ester, and a suitable protecting group.
2. The method of claim 1 , wherein R is a C4-C30 alky lsilylhydroxy alky 1.
3. The method of claim 1, wherein R is a Ci-C20 alkyl, Ci-C2O haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2- C2o alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-C2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-
Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl; and wherein each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, -SH, -OR, -SR, C-C6 alkoxy, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-Ci2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ci2 acyclic orthoester, C4-C6 cyclic orthoester, Ci-Cj2 sulfone, Cj-Ci2 sulfoxide, C2-Cj2 carbamate, C2-Ci2 urea, C2-Cj2 sulfonamide, C2-Cj2 sulfoxamide, C2-Cj2 phosphonate, C2-Ci2 phosphinoyl, and C2-Ci2 hydroxamic acid ester.
4. The method of claim 1, wherein R is chosen from a Ci-Cj2 alkyl, C8-Ci2 arylalkyl, C6-C]0 aryl, and C3-C6 cycloalkyl.
5. The method of claim 1, wherein R is chosen from a C2-Ci0 alkyl, C8-Cj2 arylalkyl, phenyl, and C5-C6 cycloalkyl.
6. The method of claim 1, wherein R is chosen from a C2-Ci0 alkyl, benzyl, phenylethyl, phenyl, and cyclohexyl.
7. The method of any one of claims 1 to 6, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (IHb), and (IIIc), in the presence of an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof.
8. The method of claim 7, wherein said organic solvent is diethylether.
9. The method of any one of claims 1 to 6, wherein said compound of formula
(II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc), in the presence of an organic solvent chosen from glyme-type solvents.
10. The method of any one of claims 7 to 9, wherein another organic solvent is further added to said organic solvent, said other organic solvent being chosen from Ci-Cio hydrocarbons.
1 1. The method of any one of claims 7 to 9, wherein another organic solvent is further added to said organic solvent, said other organic solvent being chosen from toluene, benzene, hexanes, pentane, and heptane.
12. The method of any one of claims 7 to 11 , wherein said compound of formula (II) and said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) are reacted together in said organic solvent and agitated.
13. The method of any one of claims 7 to 11, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) by preparing a composition comprising said
compound of formula (II) and said organic solvent, by adding said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) to said composition so as to obtain a mixture, and by agitating said mixture.
14. The method of any one of claims 7 to 11, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) by preparing a composition comprising said compound of formula (II) and said organic solvent, and by adding said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) dissolved in said organic solvent to said composition so as to obtain a mixture, and by agitating said mixture.
15. The method of claim 13 or 14, wherein a precipitate comprising a at least one compound chosen from M1X2, M1XT, M2X2, and M2XT is formed, and wherein a liquid phase comprising said compound of formula (I) is at least partially separated from said precipitate.
16. The method of claim 13 or 14, wherein a precipitate comprising a at least one compound chosen from M1X2, M1XT, M2X2, and M2XT is formed, and wherein said mixture is centrifuged or filtered so as to separate said precipitate from a liquid phase comprising said compound of formula (I).
17. The method of any one of claims 1 to 16, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (IHb), and (IIIc) at a temperature of about -20 °C to about 35 0C.
18. The method of any one of claims 1 to 16, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) at a temperature of about 0° C.
19. The method of any one of claims 1 to 16, wherein said compound of formula (II) is reacted with said at least one compound chosen from compounds of
formulas (Ilia), (IHb), and (HIc) at a temperature of about 0° C over a period of time of at least 5 minutes and then a heterogeneous solution so obtained is allow to stir at room temperature for a period of at least 5 minutes.
20. The method of any one of claims 1 to 19, wherein X is -OR1 in which R1 is a Ci-Ci2 alkyl, C2-Cj2 haloalkyl, C3-Ci2 alkoxyalkyl, C4-Ci2 alkylaminoalkyl, or C2-Ci2 acyl.
21. The method of any one of claims 1 to 19, wherein X is -OR1 in which R1 is RO(CH2CH2O)nCH2CH2- in which R is as previously defined and n is 1, 2 or
3.
22. The method of any one of claims 1 to 19, wherein X is -OR1 in which R1 is -CH3, W-C5Hn, (CH3)2CH-, CH3C(O)-, PhC(O)-, CF3CH2-, CH3OCH2CH2-, CH3OCH2CH2OCH2CH2-, or (CH3)2NCH2CH2-.
23. The method of any one of claims 1 to 19, wherein X is -OR1 in which R1 is -CH3, /7-C5H1,, CH3C(O)-, PhC(O)-, CF3CH2-, CH3OCH2CH2-, CH3OCH2CH2OCH2CH2-, or (CH3)2NCH2CH2-.
24. The method of any one of claim 1 to 19, wherein X is -OR1 in which R1 is -CH3.
25. The method of any one of claim 1 to 19, wherein X is acetylacetonate.
26. The method of any one of claim 1 to 19, wherein said compound of formula (II) is Zn(OCH2CH2O).
27. The method of claim 1, wherein R is chosen a C2-C20 alkenyl, C2-C20 alkynyl, C6-C20 alkylaryl, and C6-Ci2 aryl, X is -OMe, and wherein said compound of formula (II) and said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) are reacted together in the presence of NaOMe.
28. The method of claim 1, wherein R is phenyl, X is -OMe, and wherein said compound of formula (II) and said at least one compound chosen from compounds of formulas (Ilia), (HIb), and (IIIc) are reacted together in the presence of NaOMe.
29. The method of claim 1 to 28, wherein said compound of formula (II) is reacted with a compound of formula (Ilia) in which T is Br.
30. The method of any one of claims 1 to 28, wherein said compound of formula (II) is reacted with a compound of formula (Ilia) in which T is Cl.
31. A method for preparing a compound of formula (Ia):
R2ZnR3 (Ia)
wherein
R2 and R3 are the same or different and they are each a Ci-C20 alkyl, Ci- C2o haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2- C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyl)(aryl)silylalkyl, Cj9-C30 arylsilylalkyl, C4-C30
(alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6- C20 alkylaryl, C6-C20 arylalkyl, C6-Cn aryl, C2-C20 carboxylic acid ester, Ci- C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl,
said method comprising reacting a compound of formula (II) with at least one compound chosen from compounds of formulas (IHd), (HIe), and (HIf), and at least one compound chosen from compounds of formulas (HIg), (HIh), and (HIi), or with a compound of formula (IIIj):
ZnX2 (II)
R2M1T (Hid)
(R2)2M' (HIe)
(HIf)
R3M1T (HIg)
(R3)2M' (HIh)
R3M2 CIIIi)
R2M1R3 CIHj)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-Ci2 heteroarylcarboxylate, and C6-C20 arylcarboxylate, and when X is Cl or Br, a compound of formula (VI) is further added;
R2 and R3 are as previously defined;
M is Na or K;
M1 is Mg;
M2 is Li, or Na;
T is F, Cl, Br, I, OSO2R2, OR2, CN, or OC(O)R2;
R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Cj2 heterocyclyl, or
said R1 are linked together so as to form a 5 to 8 membered ring; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-C12 cycloalkyl, C1-C12 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,
(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, -SH, - OR, -SR, C1-C6 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl,
Ci-Ci2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Cj-C6 hydroxyalkyl, C2-C3 cyclic acetal, C1-C12 acetal, Ci-C]2 acyclic orthoester, C4-C6 cyclic orthoester, Ci-Ci2 sulfone, Ci-Ci2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2-C12 sulfonamide, C2-C12 sulfoxamide, C2-Cj2 phosphonate, C2-C12 phosphinoyl, C2-C12 hydroxamic acid ester, and a suitable protecting group.
32. The method of claim 31 , wherein R2 and R3 are the same or different and they are each a C1-C20 alkyl, C1-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-C12 aryl, C2-C20 carboxylic acid ester, Cj-C20 carboxylic acid amide, C3-C12 cycloalkyl, C1-C12 heteroaryl, or a C1-C12 heterocyclyl; and wherein each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid
amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, - SH, -OR, -SR, Ci-C6 alkoxy, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1- C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Cj2 heteroaryl, Ci-Ci2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, CJ-CI2 acyclic orthoester, C4-C6 cyclic orthoester, Cj-Ci2 sulfone, Ci- Ci2 sulfoxide, C2-Ci2 carbamate, C2-Ci2 urea, C2-Cj2 sulfonamide, C2-Ci2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, and C2-Cj2 hydroxamic acid ester.
33. A method for preparing a compound of formula (Ia):
R2ZnR3 (Ia)
wherein R2 and R3 are the same or different and they are each a Ci-C20 alkyl, Ci-
C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2- C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C4-C30 alkylsilylalkyl, C9-C30 (alkyl)(aryl)silylalkyl, Ci9-C30 arylsilylalkyl, C4-C30 (alkyl)(heteroaryl)silylalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6- C20 alkylaryl, C6-C20 arylalkyl, C6-Cj2 aryl, C2-C20 carboxylic acid ester, Cj-
C20 carboxylic acid amide, C3-Cj2 cycloalkyl, Cj-Ci2 heteroaryl, or a Ci-C)2 heterocyclyl,
said method comprising reacting a compound of formula (Ha) with a compound of formula (HIg), and a compound of formula (VI):
R2ZnX (Ha)
R3M1T (HIg)
MOR6 (VI)
wherein
X is chosen from -OR1, -SR1, Cl, Br, C2-C20 alkylcarboxylate, C2-C12 heteroarylcarboxylate, and C6-C20 arylcarboxylate;
R2 and R3 are as previously defined;
M1 is Mg;
M is Na or K;
T is F, Cl, Br, I, OSO2R2, OR, CN, or OC(O)R2;
R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2-
C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Cj2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Cj2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl; and
R6 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-C]2 heteroaryl, or a Ci-Ci2 heterocyclyl,
each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl, (alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, -SH, -OR,- -SR, Ci-C6
alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-Ci2 heterocyclyl, C2-C2O carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ci2 acyclic orthoester, C4- C6 cyclic orthoester, Ci-Ci2 sulfone, Ci-Ci2 sulfoxide, C2-Ci2 carbamate, C2-
Ci2 urea, C2-Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Cj2 phosphonate, C2-Ci2 phosphinoyl, C2-C]2 hydroxamic acid ester, and a suitable protecting group
34. The method of claim 33, R2 and R3 are the same or different and they are each a Cj-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl, C2-C20 alkylthioalkyl, C2-C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-C]2 heteroaryl, or a Ci-Ci2 heterocyclyl; and wherein each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, - SH, -OR,-SR, Cj-C6 alkoxy, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cr
C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, CJ-CJ2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ci2 acyclic orthoester, C4-C6 cyclic orthoester, CJ-CJ2 sulfone, C1- Ci2 sulfoxide, C2-Cj2 carbamate, C2-Ci2 urea, C2-Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Cj2 phosphonate, C2-Ci2 phosphinoyl, and C2-Cj2 hydroxamic acid ester.
35. The method of claim 33 or 34, wherein T is Cl or Br, and wherein MOR1 is NaOMe.
36. The method of any one of claims 1 to 35, further comprising carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence or absence of a metal.
37. The method of any one of claims 1 to 35, further comprising carrying out a nucleophilic addition on an organic substrate by contacting said compound of formula (I) or (Ia) with said organic substrate in the presence of a metal and a ligand.
38. The method of claim 37, wherein said metal is Cu, Ti, Ni, or Zr.
39. The method of claim 37 or 38, wherein said nucleophilic addition is a catalytic enantioselective addition.
40. The method of any one of claims 37 to 39, wherein said ligand is a chiral ligand chosen from Me-DuPHOS(O) morpholino isoborneol (MIB), dimethylaminoisoborneol (DAIB), other amino alcohol based ligands Josiphos, binap, bis(phosphine), taddol, bis(oxazoline), phosphoramidites, phosphites, diamines, PHOX, Binap(O), Binaphtol, peptide based ligands.
41. The method of any one of claims 37 to 40, wherein said nucleophilic addition is carried out on an imine, an aldehyde, a ketone, or a β-nitroalkene of said organic substrate.
42. The method of any one of claims 37 to 40, wherein said nucleophilic addition is a 1-4 addition carried out on an α,β-unsaturated aldehyde or an α,β-unsaturated ketone.
43. The method of any one of claims 1 to 35, further comprising carrying out a chemical reaction chosen from an oxidation of a diorganozinc into an alcohol, nucleophilic allylic substitution (SN2'), a transition metal catalyzed cross-coupling (for example nickel catalyzed cross-coupling or palladium
catalyzed cross-coupling), a nucleophilic substitution (for example SN2 on a ketal), an acylation, an anhydride opening, a carbozincation of an alkene or an alkyne, an allylzincation of alkenylmetal/metalla-aza-claisen, preparation of organozinc or organozinc halides, a cyclopropanation and an epoxidation, by using said compound of formula (I) or (Ia).
44. A method for preparing a compound of formula (IV):
Zn(OR!)2 (IV) wherein R1 is a Ci-C20 alkyl, Ci-C20 haloalkyl C2-C20 hydroxyalkyl, C2-C20 thioalkyl, C2-C20 aminoalkyl, C2-C20 alkoxyalkyl , C2-C20 alkylthioalkyl, C2- C20 alkylaminoalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 acyl, C6-C20 alkylaryl, C6-C20 arylalkyl, C6-Ci2 aryl, C2-C20 carboxylic acid ester, Ci-C20 carboxylic acid amide, C3-Ci2 cycloalkyl, Ci-Ci2 heteroaryl, or a Ci-Ci2 heterocyclyl, or
said R1 are linked together so as to form a 5 to 8 membered ring;
each of said alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl, being unsubstituted or substituted with at least one substituent chosen from a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, a tritium atom, -OH, -CN, -NO2, -SH, -OR, -SR, Ci-C6 alkoxy, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cj-C6 aminoalkyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-Ci2 heteroaryl, Ci-C]2 heterocyclyl, C2-C20 carboxylic acid ester, C3-C20 carboxylic acid amide, Ci-C6 hydroxyalkyl, C2-C3 cyclic acetal, Ci-Ci2 acetal, Ci-Ci2 acyclic orthoester, C4-C6 cyclic orthoester, Ci-Ci2 sulfone, Ci-Ci2 sulfoxide, C2-Ci2 carbamate,
C2-C i2 urea, C2-Ci2 sulfonamide, C2-Ci2 sulfoxamide, C2-Ci2 phosphonate, C2-Ci2 phosphinoyl, C2-Ci2 hydroxamic acid ester, and a suitable protecting group.
said method comprising reacting a compound of formula (II) with a compound of formula (V):
ZnX2 (II)
MOR1 (V)
wherein
X is Cl or Br;
M is Na or K; and
R1 is as previously defined.
45. The method of claim 44, wherein said compound of formula (II) is reacted with said compound of formula (V) in the presence of an organic solvent chosen from diethylether, t-butylmethylether, dibutylether, diphenylether, diisopropylether, dipropylether, dipentylether, dimethoxymethane, and mixtures thereof.
46. The method of claim 45, wherein said organic solvent is diethylether.
47. The method of any one of claim 44, wherein said compound of formula (II) is reacted with said compound of formula (V) in the presence of an organic solvent chosen from glyme-type solvents.
48. The method of any one of claims 45 to 47, wherein another organic solvent is further added to said organic solvent, said other organic solvent being chosen from Ci-Ci0 hydrocarbons.
49. The method of any one of claims 45 to 47, wherein another organic solvent is further added to said organic solvent, said other organic solvent being chosen from toluene, benzene, hexanes, pentane, and heptane.
50. The method of any one of claims 44 to 49, wherein R1 is CH3, and M is Na.
51. The method of any one of claims 44 to 49, wherein X is Cl.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08748265A EP2155759A4 (en) | 2007-05-07 | 2008-05-06 | Methods for preparing diorganozinc compounds |
| US12/591,108 US8492574B2 (en) | 2007-05-07 | 2009-11-09 | Methods for preparing dioranozinc compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91641907P | 2007-05-07 | 2007-05-07 | |
| US60/916,419 | 2007-05-07 |
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|---|---|---|---|
| US12/591,108 Continuation-In-Part US8492574B2 (en) | 2007-05-07 | 2009-11-09 | Methods for preparing dioranozinc compounds |
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| Publication Number | Publication Date |
|---|---|
| WO2008134890A1 true WO2008134890A1 (en) | 2008-11-13 |
Family
ID=39943091
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA2008/000864 WO2008134890A1 (en) | 2007-05-07 | 2008-05-06 | Methods for preparing diorganozinc compounds |
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|---|---|
| US (1) | US8492574B2 (en) |
| EP (1) | EP2155759A4 (en) |
| WO (1) | WO2008134890A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100990A1 (en) * | 2009-03-04 | 2010-09-10 | 国立大学法人名古屋大学 | Process for the production of nucleophilic adducts by grignard reaction, and nucleophilic addition reactant |
| WO2011002000A1 (en) | 2009-07-01 | 2011-01-06 | 三井化学株式会社 | Organometallic compounds and process for preparation thereof |
| CN102336782A (en) * | 2010-07-16 | 2012-02-01 | 国立清华大学 | Mirror selective addition method of imine |
| JP2012236818A (en) * | 2011-04-25 | 2012-12-06 | Sumitomo Chemical Co Ltd | Method for producing amine compound |
| KR101834829B1 (en) * | 2016-03-15 | 2018-03-06 | 아주대학교 산학협력단 | Organozinc compound and method for manufacturing thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3094613A4 (en) * | 2014-01-13 | 2017-06-14 | Purdue Research Foundation, Inc. | Processes for the synthesis of chiral 1-alkanols |
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| JPH02129135A (en) * | 1988-11-08 | 1990-05-17 | Ricoh Co Ltd | Novel zinc alkoxide and production thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100990A1 (en) * | 2009-03-04 | 2010-09-10 | 国立大学法人名古屋大学 | Process for the production of nucleophilic adducts by grignard reaction, and nucleophilic addition reactant |
| JP5585992B2 (en) * | 2009-03-04 | 2014-09-10 | 国立大学法人名古屋大学 | Method for producing nucleophilic adduct using Grignard reaction and nucleophilic addition reagent |
| WO2011002000A1 (en) | 2009-07-01 | 2011-01-06 | 三井化学株式会社 | Organometallic compounds and process for preparation thereof |
| US8791284B2 (en) | 2009-07-01 | 2014-07-29 | Mitsui Chemicals, Inc. | Organometallic compound and production method thereof |
| CN102336782A (en) * | 2010-07-16 | 2012-02-01 | 国立清华大学 | Mirror selective addition method of imine |
| JP2012236818A (en) * | 2011-04-25 | 2012-12-06 | Sumitomo Chemical Co Ltd | Method for producing amine compound |
| KR101834829B1 (en) * | 2016-03-15 | 2018-03-06 | 아주대학교 산학협력단 | Organozinc compound and method for manufacturing thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2155759A1 (en) | 2010-02-24 |
| EP2155759A4 (en) | 2012-10-17 |
| US8492574B2 (en) | 2013-07-23 |
| US20100121089A1 (en) | 2010-05-13 |
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