US20100144516A1 - Preparation and use of magnesium amides - Google Patents
Preparation and use of magnesium amides Download PDFInfo
- Publication number
- US20100144516A1 US20100144516A1 US12/522,494 US52249408A US2010144516A1 US 20100144516 A1 US20100144516 A1 US 20100144516A1 US 52249408 A US52249408 A US 52249408A US 2010144516 A1 US2010144516 A1 US 2010144516A1
- Authority
- US
- United States
- Prior art keywords
- solvent
- cyclic
- process according
- substituted
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- PKMBLJNMKINMSK-UHFFFAOYSA-N magnesium;azanide Chemical class [NH2-].[NH2-].[Mg+2] PKMBLJNMKINMSK-UHFFFAOYSA-N 0.000 title description 14
- 150000001408 amides Chemical class 0.000 claims abstract description 55
- 125000003118 aryl group Chemical group 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 28
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 21
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 13
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 150000007944 thiolates Chemical class 0.000 claims abstract description 6
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 140
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 72
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 72
- 239000011777 magnesium Substances 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 40
- 150000004795 grignard reagents Chemical class 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- 239000012039 electrophile Substances 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 239000007818 Grignard reagent Substances 0.000 claims description 16
- 229910003002 lithium salt Inorganic materials 0.000 claims description 16
- 159000000002 lithium salts Chemical class 0.000 claims description 16
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 14
- 239000000758 substrate Substances 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical group [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 11
- 238000010537 deprotonation reaction Methods 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 230000005595 deprotonation Effects 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 6
- BNXZHVUCNYMNOS-UHFFFAOYSA-N 1-butylpyrrolidin-2-one Chemical compound CCCCN1CCCC1=O BNXZHVUCNYMNOS-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 159000000003 magnesium salts Chemical class 0.000 claims description 6
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000003950 cyclic amides Chemical class 0.000 claims description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- HTIRHQRTDBPHNZ-UHFFFAOYSA-N Dibutyl sulfide Chemical compound CCCCSCCCC HTIRHQRTDBPHNZ-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 150000002012 dioxanes Chemical class 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical group CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003003 phosphines Chemical class 0.000 claims description 3
- 229920000570 polyether Polymers 0.000 claims description 3
- 150000003568 thioethers Chemical class 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 150000003376 silicon Chemical class 0.000 claims 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 49
- 239000002585 base Substances 0.000 description 43
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 description 32
- 238000006263 metalation reaction Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 25
- -1 alkyl lithium Chemical compound 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229910052749 magnesium Inorganic materials 0.000 description 17
- 230000009257 reactivity Effects 0.000 description 15
- 0 *N(*)[Mg]C.*N(*)[Mg]Cl.*N(*)[Mg]N(*)*.CC1(C)CCCC(C)(C)N1[Zn-](C(C)(C)C)C(C)(C)C.[Li+] Chemical compound *N(*)[Mg]C.*N(*)[Mg]Cl.*N(*)[Mg]N(*)*.CC1(C)CCCC(C)(C)N1[Zn-](C(C)(C)C)C(C)(C)C.[Li+] 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 125000001931 aliphatic group Chemical group 0.000 description 10
- 238000007306 functionalization reaction Methods 0.000 description 10
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 125000002723 alicyclic group Chemical group 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 125000000524 functional group Chemical group 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 8
- 150000008299 phosphorodiamidates Chemical class 0.000 description 8
- 238000006478 transmetalation reaction Methods 0.000 description 8
- FDDBUIWRNBGXHB-UHFFFAOYSA-N 1-iodoisoquinoline Chemical compound C1=CC=C2C(I)=NC=CC2=C1 FDDBUIWRNBGXHB-UHFFFAOYSA-N 0.000 description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000011592 zinc chloride Substances 0.000 description 7
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002879 Lewis base Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 150000007527 lewis bases Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- GWWWNAKRFFANNF-UHFFFAOYSA-N bis(dimethylamino)phosphinic acid Chemical compound CN(C)P(O)(=O)N(C)C GWWWNAKRFFANNF-UHFFFAOYSA-N 0.000 description 5
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000012964 benzotriazole Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- NFGQJEOOPQWHFX-UHFFFAOYSA-N ditert-butyl 4-iodobenzene-1,3-dicarboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=C(I)C(C(=O)OC(C)(C)C)=C1 NFGQJEOOPQWHFX-UHFFFAOYSA-N 0.000 description 3
- IHDBFNWSHXGZDC-UHFFFAOYSA-N ethyl 3-[bis(dimethylamino)phosphoryloxy]-2-iodobenzoate Chemical compound CCOC(=O)C1=CC=CC(OP(=O)(N(C)C)N(C)C)=C1I IHDBFNWSHXGZDC-UHFFFAOYSA-N 0.000 description 3
- DOLSLRDJNSIFOG-UHFFFAOYSA-N ethyl 3-[bis(dimethylamino)phosphoryloxy]benzoate Chemical compound CCOC(=O)C1=CC=CC(OP(=O)(N(C)C)N(C)C)=C1 DOLSLRDJNSIFOG-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 150000002390 heteroarenes Chemical class 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- VXLFYNFOITWQPM-UHFFFAOYSA-N n-phenyl-4-phenyldiazenylaniline Chemical compound C=1C=C(N=NC=2C=CC=CC=2)C=CC=1NC1=CC=CC=C1 VXLFYNFOITWQPM-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 2
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 2
- SOSPMXMEOFGPIM-UHFFFAOYSA-N 3,5-dibromopyridine Chemical compound BrC1=CN=CC(Br)=C1 SOSPMXMEOFGPIM-UHFFFAOYSA-N 0.000 description 2
- MVPKIPGHRNIOPT-UHFFFAOYSA-N 5,6-dimethyl-2h-benzotriazole Chemical compound C1=C(C)C(C)=CC2=NNN=C21 MVPKIPGHRNIOPT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241001120493 Arene Species 0.000 description 2
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N CC(C)(C)OC(=O)C1=CC=CC=C1 Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 2
- XCTLDQQOHIEUCJ-UHFFFAOYSA-N CCOC(=O)C1=CC=CC2=CC=CC=C21 Chemical compound CCOC(=O)C1=CC=CC2=CC=CC=C21 XCTLDQQOHIEUCJ-UHFFFAOYSA-N 0.000 description 2
- MTPLPPGNPKTJEE-UHFFFAOYSA-N CN(C)P(=O)(OC1=CC=C(C#N)C=C1)N(C)C Chemical compound CN(C)P(=O)(OC1=CC=C(C#N)C=C1)N(C)C MTPLPPGNPKTJEE-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- ZGTGCCOCZWJUCL-UHFFFAOYSA-N [Li+].[NH2-].[Mg] Chemical class [Li+].[NH2-].[Mg] ZGTGCCOCZWJUCL-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000009920 chelation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 101150008103 hal gene Proteins 0.000 description 2
- 125000005549 heteroarylene group Chemical group 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- CBOPRIUOMOZOPR-UHFFFAOYSA-N CN(C)P(=O)(OC1=CC=C(F)C=C1)N(C)C Chemical compound CN(C)P(=O)(OC1=CC=C(F)C=C1)N(C)C CBOPRIUOMOZOPR-UHFFFAOYSA-N 0.000 description 1
- DZYILDADZRQRSH-UHFFFAOYSA-N CN(C)P(=O)(OC1=CC=CC(C(F)(F)F)=C1)N(C)C Chemical compound CN(C)P(=O)(OC1=CC=CC(C(F)(F)F)=C1)N(C)C DZYILDADZRQRSH-UHFFFAOYSA-N 0.000 description 1
- JAGURCJFHWHUFA-UHFFFAOYSA-N CN(C)P(=O)(OC1=CC=CC(I)=C1)N(C)C Chemical compound CN(C)P(=O)(OC1=CC=CC(I)=C1)N(C)C JAGURCJFHWHUFA-UHFFFAOYSA-N 0.000 description 1
- GXDLNGKWABFFBR-UHFFFAOYSA-N C[Mg]C1=C(OC(=O)(N(C)C)N(C)C)C=C(C)C=C1.[H]C1=C(O[P+]([O-][Mg-](C)C)(N(C)C)N(C)C)C=C(C)C=C1 Chemical compound C[Mg]C1=C(OC(=O)(N(C)C)N(C)C)C=C(C)C=C1.[H]C1=C(O[P+]([O-][Mg-](C)C)(N(C)C)N(C)C)C=C(C)C=C1 GXDLNGKWABFFBR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KNTDMIXZSSDCAX-UHFFFAOYSA-M Cl[Mg]C1=CC(Cl)=NC(Cl)=C1 Chemical compound Cl[Mg]C1=CC(Cl)=NC(Cl)=C1 KNTDMIXZSSDCAX-UHFFFAOYSA-M 0.000 description 1
- QIKVUZKOJGBAMU-UHFFFAOYSA-M Cl[Mg]C1=CC2=C(C=CC=C2)C=C1Br Chemical compound Cl[Mg]C1=CC2=C(C=CC=C2)C=C1Br QIKVUZKOJGBAMU-UHFFFAOYSA-M 0.000 description 1
- ZNWOXBXBCDPDBL-UHFFFAOYSA-M Cl[Mg]C1=NC=C(Br)C=C1Br Chemical compound Cl[Mg]C1=NC=C(Br)C=C1Br ZNWOXBXBCDPDBL-UHFFFAOYSA-M 0.000 description 1
- JLUMTKYBWJPJKL-UHFFFAOYSA-M Cl[Mg]C1=NC=CC2=C1C=CC=C2 Chemical compound Cl[Mg]C1=NC=CC2=C1C=CC=C2 JLUMTKYBWJPJKL-UHFFFAOYSA-M 0.000 description 1
- NRXACGDFRRWWQU-UHFFFAOYSA-M Cl[Mg]C1=[Y]C2=C(C=CC=C2)C1 Chemical compound Cl[Mg]C1=[Y]C2=C(C=CC=C2)C1 NRXACGDFRRWWQU-UHFFFAOYSA-M 0.000 description 1
- FACMNXRPIJWKFU-UHFFFAOYSA-M Cl[Mg]C1=[Y]C=CC1 Chemical compound Cl[Mg]C1=[Y]C=CC1 FACMNXRPIJWKFU-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N Nc1ccccc1O Chemical compound Nc1ccccc1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ZSEBIDAZDNDAQO-UHFFFAOYSA-N [H]N(CCCCCCN(C1=NC(NC(C)(C)CC(C)(C)C)=NC(N(CCCCCCN([H])C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)=N1)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1 Chemical compound [H]N(CCCCCCN(C1=NC(NC(C)(C)CC(C)(C)C)=NC(N(CCCCCCN([H])C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)=N1)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1 ZSEBIDAZDNDAQO-UHFFFAOYSA-N 0.000 description 1
- SHPAMMOQIWIHNP-UHFFFAOYSA-N [I].C1=CC=C2C(I)=NC=CC2=C1 Chemical compound [I].C1=CC=C2C(I)=NC=CC2=C1 SHPAMMOQIWIHNP-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 150000004646 arylidenes Chemical class 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229910052790 beryllium Inorganic materials 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical group CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- JCBDRGVENJADNA-UHFFFAOYSA-N ditert-butyl benzene-1,3-dicarboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CC(C(=O)OC(C)(C)C)=C1 JCBDRGVENJADNA-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- JHBZAAACZVPPRQ-UHFFFAOYSA-L lithium;magnesium;2,2,6,6-tetramethylpiperidin-1-ide;dichloride Chemical compound [Li+].[Cl-].[Cl-].CC1(C)CCCC(C)(C)N1[Mg+] JHBZAAACZVPPRQ-UHFFFAOYSA-L 0.000 description 1
- QNRUKMBLUVIEBO-UHFFFAOYSA-L lithium;magnesium;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-] QNRUKMBLUVIEBO-UHFFFAOYSA-L 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 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
- UYYCVBASZNFFRX-UHFFFAOYSA-N n-propan-2-ylcyclohexanamine Chemical compound CC(C)NC1CCCCC1 UYYCVBASZNFFRX-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000002734 organomagnesium group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- LUYQYZLEHLTPBH-UHFFFAOYSA-N perfluorobutanesulfonyl fluoride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O LUYQYZLEHLTPBH-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical class PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 230000001960 triggered effect Effects 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
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B49/00—Grignard reactions
-
- 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
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
-
- 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
- C07F3/02—Magnesium compounds
Definitions
- the present application relates to magnesium amides, a method for the preparation of magnesium amides and the use of these amides.
- the use of lithium salts to increase the solubility of Grignard reagents is known from EP 1 582 523.
- the main function of the Grignard reagents of the general formula R*(MgX) n .LiY disclosed therein is to perform a halogen/magnesium exchange in either aliphatic or aromatic systems.
- the Grignard reagent derivatives provide a “nucleophilic carbon atom” at a magnesium-carbon-bond.
- the reactivity of the Grignard reagents can be increased by forming a magnesiate intermediate. These Grignard reagents then show a higher reactivity and selectivity due to the formation of a magnesiate intermediate.
- a further object of the present invention is to provide a magnesium base showing a high kinetic activity and a high selectivity.
- mixed magnesium and lithium amides of type R 1 R 2 N—MgX.zLiY (I) can be prepared by reacting an amine R 1 R 2 NH with a Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiY in a solvent.
- R 1 , R 2 and R′ independently are selected from substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, and, for R 1 and R 2 only, the silyl derivatives thereof.
- One of R 1 and R 2 may be H; or R 1 and R 2 together can be part of a cyclic or polymeric structure.
- X and Y may be identical or different.
- the amides of formula I can also be prepared in an alternative way by reacting a lithium amide of the formula R 1 R 2 NLi with a magnesium salt of the form MgX 2 or Mg XY. This reaction is preferably carried out in a solvent. In order to achieve a compound of formula I, the magnesium salt and the lithium amide are reacted in approximately equimolar ratio. Thus, the ratio of lithium amide to magnesium salt is usually in the range of 1:0.8-1.2, preferably in the range of 1:0.9-1.1, and most preferably in the range of 1:0.95-1.05.
- the amides of formula I are not part of the present invention.
- R 1 , R 2 , R 3 , and R 4 are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silyl derivatives thereof; and R 1 and R 2 together, and/or R 3 and R 4 together can be part of a cyclic or polymeric structure; and wherein at least one of R 1 and R 2 and at least one of R 3 and R 4 is other than H.
- the bisamides of the general formula II can be prepared from the monoamides of formula I.
- a bisamide of formula II is formed.
- This reaction is equivalent to a reaction of a generally known Grignard reagent R′MgX in the presence of an amine R 1 R 2 NH, and subsequently with R 3 R 4 NLi.
- the lithium may also be added as a lithium salt in the form LiY, especially when the Grignard reagent or the monoamide are not complexed with a lithium salt.
- the reagent may also be of the form R 1 R 2 N—MgX.zLiY, wherein a lithium salt is already present with the monoamide.
- bisamides may be prepared, wherein the two amides are different.
- the two amides may also be the same.
- the two amides are different, i.e. R 1 R 2 N is not the same as R 3 R 4 N.
- the reactivity and selectivity of the mixed magnesium lithium amides strongly depends on the one of the two amides. If both amides are identical, the difference in reactivity and selectivity can not be seen. However, if both amides differ, one of the two amides is responsible for the reactivity of the complex compound. In such a case, one of the two amide functions may be a cheap and easily introducible amide, and the other amide function may be selected for the good reactivity and selectivity.
- one of the amides is TMP and the other is diisopropyl amide.
- the magnesium amides containing two amides are referred to as bisamides, irrespective of the fact that the two amides may also be different. In the latter case, i.e. when the two amides are different, these magnesium amides may also be referred to as magnesium diamides, or heteroamides. When the two amide functions are identical, the magnesium amide may be termed as homoamide.
- the bisamides may be prepared by reacting two lithium amides R 1 R 2 NLi and R 3 R 4 NLi with a magnesium salt MgX 2 . If both lithium amides are identical, or a magnesium monoamide is reacted with a lithium amide of the same type, a bisamide of the general formula Mg(NR 1 R 2 ) 2 .zLiY will result. For a higher solubility of the magnesium salt MgX 2 , this salt may be prepared in situ, for example as described below.
- X is not present in formula II, it is defined above as it is used in the preparation of compounds of formula II.
- X may be selected from the same group as Y and may be different or identical to Y.
- the bisamides of the present invention show an increased solubility and a high reactivity.
- the amides of the present invention are bases which will tolerate many functional groups, especially halogen substituents. This is due to the different nature of the nitrogen magnesium bond present in the amides of the present application in view of a carbon magnesium bond as in Grignard reagents.
- the increase in reactivity of the Grignard reagents in the presence of a lithium salt is due to the formation of magnesiate intermediates. In contrast thereto, however, the lithium salt which is added to the amides according to the present application prevents the formation of aggregates.
- the solvent is selected from cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes, preferably 1,4-dioxane, triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide; cyclic amides, preferably N-methyl-2-pyrrolidone (NMP), N-ethyl
- the process for the preparation of amides of formula I is carried out by reacting an amine R 1 R 2 NH with a Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiY in a solvent.
- the materials are contacted preferably at room temperature for the minimum time necessary to provide the desired yield. Temperatures between 0° C. and 50° C. are preferred, however, higher or lower reaction temperatures are also suitable.
- the preparation of the bisamides of formula II is usually carried out at temperatures between ⁇ 40° C. and 50° C., preferably in the range of ⁇ 20° C. to 30° C. and most preferred at around 0° C. A person skilled in the art will, however, be able to select a suitable temperature for the preparation of the amides of formula I or II by routine experimentation.
- X and Y are independently or both Cl, Br or I, and preferably Cl.
- the preparation of a compound of formula I is achieved by iPrMgCl.LiCl [5] .
- This process is particularly preferred since iPrMgCl.LiCl is commercially available.
- any Grignard reagent can be used to prepare the mixed Mg/Li-amides in the presence of any lithium salt. It is nevertheless preferred to use a Grignard reagent the side or by-products of which can easily be removed from the reaction mixture.
- the presence of a lithium salt accelerates the exchange reaction compared to homoleptic reagents RMgX and R 2 Mg without the use of a lithium salt.
- the present invention is directed to a mixed Mg/Li bisamide of the general formula R 1 R 2 N—MgNR 3 R 4 .zLiY (II), wherein R 1 , R 2 , R 3 , R 4 , Y and z are defined as above. It is to be understood that the adduct of a solvent is also comprised by any of these formulae.
- a third aspect of the present invention is directed to a solution of the amide (II) in a solvent.
- the solvent can be any suitable solvent capable of dissolving the amide.
- Especially preferred solvents are the solvents listed above for the preparation of the amides.
- the solvent used to dissolve the mixed amides or used for the solvent adduct of the mixed amides contains a Lewis base.
- a Lewis base in the understanding of the present application is a molecule having an electron lone pair in a bonding orbital.
- a specifically preferred Lewis base for the amides of the present invention is THF.
- Other preferred Lewis bases may be selected from 2-methyl THF, dioxane, mixtures of THF and/or 2-methyl THF with dioxane, mixtures of pentane and/or hexane with THF and/or 2-methyl THF, and any mixture of the compounds, selected from diethylether, diisopropylether, di-n-butyl ether, cyclopentylmethyl ether, methyl tert-butyl ether, THF and 2-methyl THF.
- the Lewis base is present in an amount of 4-30 eq, preferably in an amount of 4.5-20 eq, even more preferably in an amount of 5-15 eq, and most preferably in an amount of 5-10 eq, in relation to the amount of Mg in the amide.
- the present invention is related to the use of mixed Mg/Li amides (II).
- the amides of the present invention can be used to remove acidic protons.
- the deprotonated species can then subsequently be quenched with an electrophile.
- electrophiles that are, for example, cited in the following references, but are not limited thereto:
- the bisamides of the present invention combine a high reactivity at a high selectivity or tolerance towards other functional groups within a molecule. Especially, this effect can be seen with aromatic reagents substituted with sensitive functional groups. These aromatic, or heteroaromatics, need a highly reactive base to be deprotonated, and at the same time, the base has to tolerate other functional groups like esters or nitriles. Benzonitrile or benzoic acid esters are examples of such compounds. These aromatic compounds can be deprotonated with common bases like LDA, LiHMDS oder n-BuLi, however, the bases will not tolerate any other functional groups within the reagent.
- magnesium monoamides like TMPMgCl.LiCl are too unreactive to deprotonate the aromatic reagent.
- the base has to be added in a high surplus, needing a surplus of the electrophile.
- the new bisamides of the present invention give a solution to this problem as these compounds combine a high reactivity at a high selectivity.
- a preferred embodiment of the present invention refers to the use of magnesium bisamides of the present invention for the deprotonation of aromatics and heterocycles.
- the aromatics or heterocycles are substituted with a phosphorodiamidate, more preferably with tetramethylphosphorodiamidate.
- Phosphorodiamidates can be used as directing metalation groups (DMG) and allow a substitution pattern of the aromatics or heterocyles which would otherwise not be possible.
- the final aspect of the invention relates to the product of the reaction of an electrophile with a substrate which has been deprotonated with a reagent of the general formula II.
- z is preferably in the range of from 0.01-5, more preferably, z>1, more preferably, z is in the range from 1-5, more preferably from 0.5-2.5, further more preferably from 1.5 to 2.5, even more preferably from 1.8 to 2.2, even further more preferably from 1.9 to 2.1, still even more preferably from 1.95 to 2.05, and most preferred about 2.
- the lithium salt is most preferably used in an equal amount in relation to the amide function of the bisamide.
- the amount of lithium salt is thus most preferably about 2, however, a slight deviation of this optimum value still leads to acceptable results.
- the present invention is described in the following on the basis of specific examples. Especially, i-PrMgCl is used as Grignard reagent. However, it is to be understood that the present invention is not limited to such examples.
- alkyl refers to linear, cyclic and branched, substituted and unsubstitued C 1 -C 20 compounds. Preferred ranges for these compounds are C 1 -C 10 , preferably C 1 -C 5 (lower alkyl) and C 2 -C 10 and preferably C 2 -C 5 , respectively, for alkenyl and alkynyl.
- cycloalkyl generally refers to linear and branched, substituted and unsubstitued C 3 -C 20 cycloalkanes.
- preferred ranges are C 3 -C 15 , more preferably C 3 -C 8 .
- the substituent may be selected by a person skilled in the art from any known substituent.
- a person skilled in the art will select a possible substituent according to his knowledge and will be able to select a substituent which will not interfere with other substituents present in the molecule and which will not interfere or disturb possible reactions, especially the reactions described within this application.
- Possible substituents include without limitation
- the substituents may be bound to the residues R 1 , R 2 , R 3 and/or R 4 via a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom.
- the hetero atoms in any structure containing hetero atoms, as e.g. heteroarylenes or heteroaromatics, may preferably be N, O, S and P.
- R 1 and R 2 , or R 3 and R 4 can be part of a cyclic structure
- R 1 and R 2 together, or R 3 and R 4 together are a divalent saturated or unsaturated, linear or branched alkyl, alkenyl or alkynyl which forms in connection with the nitrogen atom of the amide a cyclic secondary amide.
- An example of such a cyclic amide is the amide of TMPH.
- the residues R 1 and R 2 , and/or R 3 and R 4 can be part of a polymeric structure.
- the nitrogen atom of the amide is the connected to a polymeric backbone which may even contain more than one nitrogen atom for the formation of an amide according to the invention.
- aryl refers to substituted or unsubstituted C 4 -C 24 aryl.
- heteroaryl a substituted or unsubstituted C 3 -C 24 aryl, containing one or more heteroatoms as B, O, N, S, Se, P, is meant.
- Preferred ranges for both are C 4 -C 15 , more preferably C 4 -C 10 and includes aryls and fused aryls with or without heteroatoms.
- a preferred ring size comprises 5 or 6 ring atoms.
- i-PrMgCl.LiCl [4,5] diisopropylamine or 2,2,6,6-tetramethylpiperidine (TMPH), respectively, in THF ( ⁇ 20° C.-80° C., for 0.1-48 h).
- the activity of the amides (I) can be shown on the basis of the magnesiation of isoquinoline.
- Diisopropylamido magnesium chloride-lithium chloride 5a leads to the magnesiated isoquinoline 6 after 12 h reaction time at 25° C. and by using 2 equivalents of the base.
- the iodoisoquinoline 7a is isolated in 88% yield (Scheme 2).
- Even more active is the sterically more hindered and less aggregated 2,2,6,6-tetramethylpiperidino magnesium chloride-lithium chloride reagent 5b. It leads to a complete magnesiation within 2 h at 25° C.
- the magnesiation of heterocycles bearing more acidic protons [7] such as thiazole, thiophene, furan, benzothiophene or benzothiazole proceeds smoothly between 0° C. and 25° C. leading to the organomagnesium derivatives 14a-c and 16a-b. After trapping with standard electrophiles, the expected products 15a-c and 17a-b are obtained in 81-98% yield (entries 10-14 of Table 1).
- the metalation of pyrimidine derivatives is a challenging problem due to the propensity of these heterocycles to add organometallic reagents.
- the inventors found that the inverse addition of the pyrimidine derivatives 18-20 to a THF solution of 5b (1.05 equiv.) at ⁇ 55° C. for approx. 5 min. provides the corresponding magnesiated derivatives 21-23 in 83-90% yields as indicated by iodolysis experiments leading to the iodinated pyrimidines 24-26 (scheme 3).
- the mixed magnesium-lithium amide 5b is also well suited for the regioselective metalation of polyfunctional aromatic systems.
- the reaction of 2-phenylpyridine 27 in THF at 55° C. with 5b (2.0 equiv.) for 24 h provides the Grignard reagent 28 showing a rare case where a phenyl ring is preferentially metalated compared to a pyridine ring.
- the ortho-iodinated product 29 is obtained in 80% yield.
- the metalation of polyfunctional aromatics such as the bromodiester 30 also succeeds using only the stoichiometric amount of base 5b (1.1 equiv.) in THF ( ⁇ 30° C., 0.5 h) leading regioselectively to the arylmagnesium species 31 which after iodolysis furnishes the polyfunctional aromatic derivative 32 in 88% yield.
- TMPMgCl.LiCl A solution of TMPMgCl.LiCl can easily be prepared in THF due to its excellent solubility and it is stable for more than 6 months at 25° C.
- the use of TMPMgCl.LiCl allows for the regioselective functionalization of various aromatics and heteroaromatics. It gives access to new magnesium species not readily available via a Br/Mg-exchange reactions or by previously reported metalation procedures.
- R 1 and R 2 are not limited to organic compounds.
- R 1 and R 2 may also be silylated compounds like trimethylsilyl.
- the preparation of the bis(trimethylsilyl) amide 33 can be achieved by reacting bis(trimethylsilyl)amine with i-PrMgCl.LiCl at room temperature (see Scheme 5). This base can efficiently be used to deprotonate ketones like e.g. cyclohexanone as can be seen from Scheme 5.
- the Grignard reagents can also be used to prepare a polymeric base.
- 2,2,6,6-Tetramethyl piperidine (TMPH) is a well known base. It can be used to prepare the corresponding mixed Mg/Li amide TMPMgCl.LiCl 5b. This monomeric base is very reactive but also very expensive.
- a corresponding polymeric base to TMPH is chimassorb 994, the structure of which is shown in Scheme 6.
- Chimassorb 994 can be used to prepare the corresponding mixed Mg/Li amide by reacting chimassorb 994 with i-PrMgCl.LiCl at room temperature (see Scheme 5).
- This base 34 is stable and soluble in THF before and after deprotonation. As being a polymeric base, it can be easily removed after completion of the reaction. Since chimassorb 994 is much cheaper than TMP, a corresponding base can be prepared at reduced costs.
- the polymeric base 34 shows slightly lower activity than monomeric TMPMgCl.LiCl but is nevertheless very effective in deprotonating compounds with acidic protons like isoquinoline. A corresponding example is shown in Scheme 7.
- the polymeric base can be used to deprotonate various substrates. For example, isoquinoline reacts at room temperature with the base 34 affording after quenching with iodine 1-iodoisoquinoline 7a.
- TMP 2,2,6,6-tetramethylpiperidide
- Scheme 10 gives an overview over examples of reactions of four different aromatic substances (41-44) with (TMP) 2 Mg.2LiCl (40a) and TMPMgCl.LiCl (5b) under identical conditions. The respective yields are indicated for the products of each of the two amides 40a and 5b. This experiment clearly shows the even superior reactivity of the bisamides in view of the monoamides. All reactions are carried out at room temperature (rt) being at 25° C.
- the unsymmetrical reagents 40e-40i are prepared from TMPMgCl.LiCl, i-Pr 2 NMgCl.LiCl and (2-ethyl-hexyl) 2 NMgCl.LiCl [9] , respectively, and the corresponding lithium species of 1H-benzotriazole (Bt), 5,6-dimethyl-1H-benzotriazole (DMBt) and carbazole (CBZ), respectively (Scheme 11).
- the base 40e provides a far higher reactivity than TMPMgCl.LiCl (5b) and (TMP) 2 Mg.2LiCl (40a) when using special directing metalation groups (DMG).
- TMPMgCl.LiCl provides full metalation of 44 in 90 minutes at 0° C.
- reagent 40a provides full metalation in 60 minutes.
- the use of 40e provides full metalation at 0° C. in only 10 minutes.
- only 1.3 equivalents of the base 40e are used in contrast to 1.5 equivalents of TMPMgCl.LiCl.
- the yield of 44a is higher compared to the use of TMPMgCl.LiCl (Scheme 12).
- the regulating intermediates derived from (TMP)Mg(Bt).2LiCl show good stability and tolerance to various substrates. They can be trapped with an electrophile like iodine to provide the corresponding functionalized derivatives in good yields. Examples are shown in Table 3.
- the compounds of the present invention can also be used in connection with a phosphorodiamidate group on an aryl or heteroaryl. This effect will be shown in the following with the N,N,N′,N′-tetramethylphosphorodiamidate ((Me 2 N) 2 P(O)O—) group, but is not limited to this specific group. As a person skilled in the art will recognize immediately, other directing metalation groups can also be used, especially other phosphorodiamidate groups.
- Ortho-directed metalation is an important method for the functionalization of various aromatics and heterocycles.
- Various DMG directed metalation groups
- the DMG allow for a fast and ortho-selective metalation mainly by chelation (entropic effect).
- Polar DMG may furthermore transfer electron density to the metal base and increase their metalating power.
- magnesiate bases have proven to be of great structural and synthetic interest for the functionalization of aromatics.
- mixed Li, Mg-bases like TMP 2 Mg.2LiCl are highly active and soluble magnesium bases allowing for smooth metalations of various aromatics and heterocycles with an excellent functional group compatibility.
- the inventors found that the DMG N,N,N′,N′ tetramethylphosphorodiamidate ((Me 2 N) 2 P(O)O—) is a very strong directing group for magnesiation an it may overrule the effect of other substituents present in the aromatic substrate. In contrast to directed lithiations, which have usually to be performed at ⁇ 105° C.
- the magnesiation of substrates 61 and 62 using TMP 2 Mg.2LiCl (40a) proceeds smoothly within a few hours at 0° C. for cyano- and ester-substituted phosphorodiamidates 60a and 61a (entries 1-3, 10-13).
- This electronic effect increases the metalation power of the base and no additional chelation or inductive effects are necessary for achieving the magnesiation.
- this phosphorodiamidate-triggered magnesiation preferentially occurs at the sterically less hindered position of the aromatic ring promoting formal meta-metalation.
- the inventors observed that the regioselectivity of the metalation is affected by the competitive directing effects of these halogens.
- the ketone 62a was converted to the diketone 66a in 77% yield. Furthermore, the double functionalization of the bromo- and chloro-substituted phosphorodiamidates 60b and 60d led to the preparation of the highly functionalized phosphorodiamidates 66b and 66c in good overall yields, showing the high directing power of the OP(O)(NMe 2 ) 2 group (Scheme 15).
- this approach allows to achieve new functionalization pattern of aromatics by performing magnesiations using the powerful TMP 2 Mg.2LiCl base (40a) combined with the phosphorodiamidate (—OP(O)(NMe 2 ) 2 ) as strong directing metalation group.
- This methodology allows a general preparation of various meta-, para- and meta, meta′-polyfunctionalized aromatics which are not easily accessible by using conventional synthetic strategies. Applications toward the synthesis of biologically active molecules seem to be feasible with this approach.
- the new mixed Mg/Li-bases are very effective in deprotonating organic compounds.
- the deprotonation can be achieved in different solvents and can preferably be conducted at temperatures between ⁇ 90° C. and 100° C.
- the amides of the present invention preferably only require the use of 0.9-5 equivalents, more preferably 1-2 equivalents and most preferably 1.1-1.5 equivalents per proton to be deprotonated.
- reaction mixture was quenched with sat. aqueous NH 4 Cl solution (10 mL).
- aqueous phase was extracted with ether (4 ⁇ 10 mL), dried with Na 2 SO 4 and concentrated in vacuo.
- the MgCl 2 solution was then transferred via cannula into the TMPLi solution and the reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for an additional 1 h. The solvents were removed then in vacuo followed by addition of THF while stirring until complete dissolution of the salts.
- the fresh (TMP) 2 Mg.2LiCl solution was titrated prior to use at 0° C. against benzoic acid using 4-(phenylazo)-diphenylamine as indicator.Average concentration in THF was 0.6 mol/1.
- Benzotriazole (Bt)(1.19 g, 10.0 mmol) was placed in a flame dried, argon flushed 50 ml Schlenk tube equipped with magnetic stirring bar and septum. THF (10 ml) was added. The solution was cooled to ⁇ 40° C. Then n-BuLi (3.62 ml, 2.76 M in hexane, 10.0 mmol) was added drop wise. White precipitate was formed immediately. After the end of the addition the resulting suspension was stirred at ⁇ 40° C. for 30 min. Then solvents were removed in vacuo followed by addition of TMPMgCl.LiCl (8.93 ml, 1.12 M in THF, 10.0 mmol).
- THF was removed in vacuo. To the resulting brownish gel, THF was added while stirring until complete dissolution of the salts.
- the fresh (TMP)Mg(Bt).2LiCl solution was titrated at room temperature against benzoic acid using 4-(phenylazo)-diphenylamine as an indicator. Average concentration in THF was found to be 0.35 mol/1.
- TMPH 2,2,6,6-tetramethylpiperidine
- the aryl phosphorodiamidate 60d (2.62 g, 8.00 mmol) was dissolved in THF (8 mL), cooled to ⁇ 40° C. and TMP 2 Mg.2LiCl (0.6 M in THF, 14.7 mL, 8.8 mmol) was added dropwise. The mixture was stirred at ⁇ 40° C. for 1.5 h. Complete metalation was detected by GC-analysis of reaction aliquots which were quenched with I 2 in dry THF. A solution of ZnCl 2 (1 M in THF, 9.6 mL, 9.6 mmol) was added dropwise, and the resulting mixture stirred for 15 min.
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Abstract
The present application relates to mixed Mg/Li amides of the general formula R1R2N—Mg—NR3R4.zLiY (II) wherein R1, R2, R3, and R4 are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silyl derivatives thereof; and R1 and R2 together, or R3 and R4 together can be part of a cyclic or polymeric structure; and wherein at least one of R1 and R2 and at least one of R3 and R4 is other than H; Y is selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HaIOn, wherein n=3 or 4 and Hal is selected from Ci, Br and I; NO3; BF4; PF6; H; a carboxylate of the general formula RxCO2; an alcoholate of the general formula ORx; a thiolate of the general formula SRx; RxP(O)O2; or SCORx; or SCSRx; OnSRx, wherein n=2 or 3; or NOn, wherein n=2 or 3; and a derivative thereof; wherein RX is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, or H; m is O or 1; and z>1; as well as a process for the preparation of the mixed Mg/Li amides and the use of these amides, e.g. as bases.
Description
- The present application relates to magnesium amides, a method for the preparation of magnesium amides and the use of these amides.
- The metalation of aromatics is one of the most useful transformations in organic synthesis since it allows the regioselective functionalization of various aryl derivatives.[1] Traditionally, strong bases such as alkyl lithium (RLi) or lithium amides (R2NLi) have been used to perform such deprotonations. However, these highly reactive bases display often undesirable side reactions due to the too high reactivity of the resulting aryl lithium compounds. Another serious limitation is the low stability of lithium amides in THF solutions at room temperature which requires an in situ generation of these reagents. Furthermore, the deprotonation of aromatics by lithium bases often requires very low temperatures (−78° C. to −90° C.) which complicates the scale-up of these reactions and the use of solvent mixtures such as THF/pentane may be needed.
- Alternative methods have been developed using magnesium amides[2] such as compounds 1-3 or amido zincates[3] 4 (see Scheme 1). The low solubility of the magnesium amides R2NMgCL (1) could be improved by Eaton who developed the use of magnesium amides of type R2NMgR′ (2) and (R2N)2Mg (3). Nevertheless, for achieving high conversions it is usually necessary to use a large excess of the magnesium amides (2-8 equivalents), which complicates further quenching reactions with electrophiles (up to 15 equivalents of electrophile may have to be used). Similarly, the dialkyl amino zincate 4 requires the use of 3.5-4 equivalents of an electrophile in subsequent quenching reactions.
- The use of these bases is thus either limited by their poor solubility, or they are not very efficient in view of the amounts of base and the amount of electrophile needed to perform the desired conversion. Their activity or reactivity is very low.
- The use of lithium salts to increase the solubility of Grignard reagents is known from EP 1 582 523. In this application, the main function of the Grignard reagents of the general formula R*(MgX)n.LiY disclosed therein is to perform a halogen/magnesium exchange in either aliphatic or aromatic systems. The Grignard reagent derivatives provide a “nucleophilic carbon atom” at a magnesium-carbon-bond. By the addition of a lithium salt to the Grignard reagent, the reactivity of the Grignard reagents can be increased by forming a magnesiate intermediate. These Grignard reagents then show a higher reactivity and selectivity due to the formation of a magnesiate intermediate.
- It is an object of the present invention to provide an inexpensive magnesium base which is highly soluble and more reactive. A further object of the present invention is to provide a magnesium base showing a high kinetic activity and a high selectivity.
- These objects are achieved by the features of the independent claims. Preferred embodiments are set forth in the dependent claims.
- Surprisingly, it was found and reported in an older patent application published as EP 1810974 A1 that mixed magnesium and lithium amides of type R1R2N—MgX.zLiY (I) can be prepared by reacting an amine R1R2NH with a Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiY in a solvent.
- R1, R2 and R′ independently are selected from substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, and, for R1 and R2 only, the silyl derivatives thereof. One of R1 and R2 may be H; or R1 and R2 together can be part of a cyclic or polymeric structure.
- X and Y independently are selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalOn, wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO3; BF4; PF6; H; a carboxylate of the general formula RXCO2; an alcoholate of the general formula ORX; a thiolate of the general formula SRX; RXP(O)O2; or SCORX; OnSRX, wherein n=2 or 3; or NOn, wherein n=2 or 3; and a derivative thereof; wherein RX is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms; linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof; or H.
- X and Y may be identical or different. In the above given context, z>0.
- The amides of formula I can also be prepared in an alternative way by reacting a lithium amide of the formula R1R2NLi with a magnesium salt of the form MgX2 or Mg XY. This reaction is preferably carried out in a solvent. In order to achieve a compound of formula I, the magnesium salt and the lithium amide are reacted in approximately equimolar ratio. Thus, the ratio of lithium amide to magnesium salt is usually in the range of 1:0.8-1.2, preferably in the range of 1:0.9-1.1, and most preferably in the range of 1:0.95-1.05.
- The amides of formula I are not part of the present invention.
- Now, additionally, the inventors found that magnesium bisamides of the general formula
-
R1R2N—Mg—NR3R4 .zLiY (II) - can be prepared. In this formula, R1, R2, R3, and R4 are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silyl derivatives thereof; and R1 and R2 together, and/or R3 and R4 together can be part of a cyclic or polymeric structure; and wherein at least one of R1 and R2 and at least one of R3 and R4 is other than H.
- X and Y are, independently, selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalOn, wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO3; BF4; PF6; H; a carboxylate of the general formula RXCO2; an alcoholate of the general formula ORX; a thiolate of the general formula SRX; RXP(O)O2; or SCORX; or SCSRX; OnSRX, wherein n=2 or 3; or NOR, wherein n=2 or 3; and a derivative thereof; wherein RX is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, or H;
- In the above given formula II, z>0. The adduct with a solvent should also be encompassed by any of the compounds of formula II.
- The bisamides of the general formula II can be prepared from the monoamides of formula I. When reacting R1R2N—MgX.zLiY with R3R4NLi, a bisamide of formula II is formed. This reaction is equivalent to a reaction of a generally known Grignard reagent R′MgX in the presence of an amine R1R2NH, and subsequently with R3R4NLi. The lithium may also be added as a lithium salt in the form LiY, especially when the Grignard reagent or the monoamide are not complexed with a lithium salt. Obviously, the reagent may also be of the form R1R2N—MgX.zLiY, wherein a lithium salt is already present with the monoamide. In this way, bisamides may be prepared, wherein the two amides are different. However, the two amides may also be the same.
- In a preferred embodiment of the present invention, the two amides are different, i.e. R1R2N is not the same as R3R4N. The reactivity and selectivity of the mixed magnesium lithium amides strongly depends on the one of the two amides. If both amides are identical, the difference in reactivity and selectivity can not be seen. However, if both amides differ, one of the two amides is responsible for the reactivity of the complex compound. In such a case, one of the two amide functions may be a cheap and easily introducible amide, and the other amide function may be selected for the good reactivity and selectivity. In a specifically preferred embodiment of the present invention, one of the amides is TMP and the other is diisopropyl amide.
- In the following description, the magnesium amides containing two amides are referred to as bisamides, irrespective of the fact that the two amides may also be different. In the latter case, i.e. when the two amides are different, these magnesium amides may also be referred to as magnesium diamides, or heteroamides. When the two amide functions are identical, the magnesium amide may be termed as homoamide.
- Alternatively, the bisamides may be prepared by reacting two lithium amides R1R2NLi and R3R4NLi with a magnesium salt MgX2. If both lithium amides are identical, or a magnesium monoamide is reacted with a lithium amide of the same type, a bisamide of the general formula Mg(NR1R2)2.zLiY will result. For a higher solubility of the magnesium salt MgX2, this salt may be prepared in situ, for example as described below.
- Even though X is not present in formula II, it is defined above as it is used in the preparation of compounds of formula II. X may be selected from the same group as Y and may be different or identical to Y.
- The bisamides of the present invention show an increased solubility and a high reactivity. Unlike Grignard reagents, which can perform halogen/magnesium exchanges, the amides of the present invention are bases which will tolerate many functional groups, especially halogen substituents. This is due to the different nature of the nitrogen magnesium bond present in the amides of the present application in view of a carbon magnesium bond as in Grignard reagents. The increase in reactivity of the Grignard reagents in the presence of a lithium salt is due to the formation of magnesiate intermediates. In contrast thereto, however, the lithium salt which is added to the amides according to the present application prevents the formation of aggregates. The formation of aggregates is a well known problem in the background art in relation to magnesium amides. As a consequence, the amides known so far have to be used in high excess as they are not very reactive. As the amides of the present invention are not present as aggregates due to the presence of a lithium salt, the amides are much more reactive and more soluble than the amides known so far.
- Many common solvents can be used in the present invention. In principle, any solvent capable of dissolving the specific amine and the Grignard reagent used as starting materials and the resulting products. In a preferred embodiment of the present invention, the solvent is selected from cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes, preferably 1,4-dioxane, triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide; cyclic amides, preferably N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP); cyclic, linear or branched alkanes and/or alkenes wherein one or more hydrogens are replaced by a halogen, preferably dichloromethane, 1,2-dichloroethane, CCl4; urea derivatives, preferably N,N′-dimethylpropyleneurea (DMPU); aromatic, heteroaromatic or aliphatic hydrocarbons, preferably benzene, toluene, xylene, pyridine, pentane, cyclohexane, hexane, heptane; hexamethylphosphorus triamide (HMPA), CS2; or combinations thereof.
- The process for the preparation of amides of formula I, which is not part of this application, is carried out by reacting an amine R1R2NH with a Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiY in a solvent. The materials are contacted preferably at room temperature for the minimum time necessary to provide the desired yield. Temperatures between 0° C. and 50° C. are preferred, however, higher or lower reaction temperatures are also suitable. The preparation of the bisamides of formula II is usually carried out at temperatures between −40° C. and 50° C., preferably in the range of −20° C. to 30° C. and most preferred at around 0° C. A person skilled in the art will, however, be able to select a suitable temperature for the preparation of the amides of formula I or II by routine experimentation.
- In another preferred embodiment, X and Y are independently or both Cl, Br or I, and preferably Cl.
- Preferably, the preparation of a compound of formula I is achieved by iPrMgCl.LiCl[5]. This process is particularly preferred since iPrMgCl.LiCl is commercially available.
- Generally, any Grignard reagent can be used to prepare the mixed Mg/Li-amides in the presence of any lithium salt. It is nevertheless preferred to use a Grignard reagent the side or by-products of which can easily be removed from the reaction mixture. The presence of a lithium salt accelerates the exchange reaction compared to homoleptic reagents RMgX and R2Mg without the use of a lithium salt.
- According to a second aspect, the present invention is directed to a mixed Mg/Li bisamide of the general formula R1R2N—MgNR3R4.zLiY (II), wherein R1, R2, R3, R4, Y and z are defined as above. It is to be understood that the adduct of a solvent is also comprised by any of these formulae.
- A third aspect of the present invention is directed to a solution of the amide (II) in a solvent. The solvent can be any suitable solvent capable of dissolving the amide. Especially preferred solvents are the solvents listed above for the preparation of the amides.
- All aspects and features described above in relation to the first aspect shall also apply to the second and third aspect of the invention.
- In a preferred embodiment of the present invention, the solvent used to dissolve the mixed amides or used for the solvent adduct of the mixed amides contains a Lewis base. A Lewis base in the understanding of the present application is a molecule having an electron lone pair in a bonding orbital. A specifically preferred Lewis base for the amides of the present invention is THF. Other preferred Lewis bases may be selected from 2-methyl THF, dioxane, mixtures of THF and/or 2-methyl THF with dioxane, mixtures of pentane and/or hexane with THF and/or 2-methyl THF, and any mixture of the compounds, selected from diethylether, diisopropylether, di-n-butyl ether, cyclopentylmethyl ether, methyl tert-butyl ether, THF and 2-methyl THF.
- In another preferred embodiment of the present invention, the Lewis base is present in an amount of 4-30 eq, preferably in an amount of 4.5-20 eq, even more preferably in an amount of 5-15 eq, and most preferably in an amount of 5-10 eq, in relation to the amount of Mg in the amide. With such a high amount of Lewis base, stable mixed amides can more easily be produced and can be maintained without any deterioration for longer times.
- In a fourth aspect, the present invention is related to the use of mixed Mg/Li amides (II). The amides of the present invention can be used to remove acidic protons. The deprotonated species can then subsequently be quenched with an electrophile. In principle it is possible to use all kinds of electrophiles that are, for example, cited in the following references, but are not limited thereto:
- a) Handbook of Grignard reagents; edited by Gary S. Silverman and Philip E. Rakita (Chemical industries; v. 64).
- b) Grignard reagents New Developments; edited by Herman G. Richey, Jr., 2000, John Wiley & Sons Ltd.
- c) Methoden der Organischen Chemie, Houben-Weyl, Band XIII/2a, Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd. 1973.
- d) The chemistry of the metal-carbon bond, vol 4. edited by Frank R. Hartley. 1987, John Wiley & Sons.
- The bisamides of the present invention combine a high reactivity at a high selectivity or tolerance towards other functional groups within a molecule. Especially, this effect can be seen with aromatic reagents substituted with sensitive functional groups. These aromatic, or heteroaromatics, need a highly reactive base to be deprotonated, and at the same time, the base has to tolerate other functional groups like esters or nitriles. Benzonitrile or benzoic acid esters are examples of such compounds. These aromatic compounds can be deprotonated with common bases like LDA, LiHMDS oder n-BuLi, however, the bases will not tolerate any other functional groups within the reagent. On the other hand, magnesium monoamides like TMPMgCl.LiCl are too unreactive to deprotonate the aromatic reagent. As a consequence, the base has to be added in a high surplus, needing a surplus of the electrophile. The new bisamides of the present invention give a solution to this problem as these compounds combine a high reactivity at a high selectivity.
- A preferred embodiment of the present invention refers to the use of magnesium bisamides of the present invention for the deprotonation of aromatics and heterocycles. Preferably, the aromatics or heterocycles are substituted with a phosphorodiamidate, more preferably with tetramethylphosphorodiamidate. Phosphorodiamidates can be used as directing metalation groups (DMG) and allow a substitution pattern of the aromatics or heterocyles which would otherwise not be possible.
- The final aspect of the invention relates to the product of the reaction of an electrophile with a substrate which has been deprotonated with a reagent of the general formula II.
- In relation to the bisamide of formula II, z is preferably in the range of from 0.01-5, more preferably, z>1, more preferably, z is in the range from 1-5, more preferably from 0.5-2.5, further more preferably from 1.5 to 2.5, even more preferably from 1.8 to 2.2, even further more preferably from 1.9 to 2.1, still even more preferably from 1.95 to 2.05, and most preferred about 2.
- The inventors of the present invention surprisingly found that the lithium salt is most preferably used in an equal amount in relation to the amide function of the bisamide. For the bisamides, the amount of lithium salt is thus most preferably about 2, however, a slight deviation of this optimum value still leads to acceptable results.
- The present invention is described in the following on the basis of specific examples. Especially, i-PrMgCl is used as Grignard reagent. However, it is to be understood that the present invention is not limited to such examples.
- Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications and other references mentioned herein are incorporated by reference in their entirety.
- As used herein, the terms “alkyl”, “alkenyl” and “alkynyl” refer to linear, cyclic and branched, substituted and unsubstitued C1-C20 compounds. Preferred ranges for these compounds are C1-C10, preferably C1-C5 (lower alkyl) and C2-C10 and preferably C2-C5, respectively, for alkenyl and alkynyl. The term “cycloalkyl” generally refers to linear and branched, substituted and unsubstitued C3-C20 cycloalkanes. Here, preferred ranges are C3-C15, more preferably C3-C8.
- Whenever any of the residues R1, R2, R3 and/or R4 are substituted by a substituent, the substituent may be selected by a person skilled in the art from any known substituent. A person skilled in the art will select a possible substituent according to his knowledge and will be able to select a substituent which will not interfere with other substituents present in the molecule and which will not interfere or disturb possible reactions, especially the reactions described within this application. Possible substituents include without limitation
-
- halogens, preferably fluorine, chlorine, bromine and iodine;
- aliphatic, alicyclic, aromatic or heteroaromatic hydrocarbons, especially alkanes, alkylenes, arylenes, alkylidenes, arylidenes, heteroarylenes and heteroarylidenes;
- carbonxylic acids including the salts thereof;
- carboxylic acid halides;
- aliphatic, alicyclic, aromatic or heteroaromatic carboxylilc acid esters;
- aldehydes;
- aliphatic, alicyclic, aromatic or heteroaromatic ketones;
- alcohols and alcoholates, including a hydroxyl group;
- phenoles and phenolates;
- aliphatic, alicyclic, aromatic or heteroaromatic ethers;
- aliphatic, alicyclic, aromatic or heteroaromatic peroxides;
- hydroperoxides;
- aliphatic, alicyclic, aromatic or heteroaromatic amides or amidines;
- nitriles;
- aliphatic, alicyclic, aromatic or heteroaromatic amines;
- aliphatic, alicyclic, aromatic or heteroaromatic imines;
- aliphatic, alicyclic, aromatic or heteroaromatic sulfides including a thiol group;
- sulfonic acids including the salts thereof;
- thioles and thiolates;
- phosphonic acids including the salts thereof;
- phosphinic acids including the salts thereof;
- phosphorous acids including the salts thereof;
- phosphinous acids including the salts thereof;
- The substituents may be bound to the residues R1, R2, R3 and/or R4 via a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom. The hetero atoms in any structure containing hetero atoms, as e.g. heteroarylenes or heteroaromatics, may preferably be N, O, S and P.
- When R1 and R2, or R3 and R4 can be part of a cyclic structure, it is to be understood that R1 and R2 together, or R3 and R4 together, are a divalent saturated or unsaturated, linear or branched alkyl, alkenyl or alkynyl which forms in connection with the nitrogen atom of the amide a cyclic secondary amide. An example of such a cyclic amide is the amide of TMPH. Further, the residues R1 and R2, and/or R3 and R4 can be part of a polymeric structure. The nitrogen atom of the amide is the connected to a polymeric backbone which may even contain more than one nitrogen atom for the formation of an amide according to the invention.
- The term “aryl” as used herein refers to substituted or unsubstituted C4-C24 aryl. By “heteroaryl”, a substituted or unsubstituted C3-C24 aryl, containing one or more heteroatoms as B, O, N, S, Se, P, is meant. Preferred ranges for both are C4-C15, more preferably C4-C10 and includes aryls and fused aryls with or without heteroatoms. A preferred ring size comprises 5 or 6 ring atoms.
- Mixed magnesium and lithium amides R1R2NMgCl.LiCl (R1 and R2=i-Pr or R1R2N=2,2,6,6-tetramethylpiperidyl) can be prepared by reacting i-PrMgCl.LiCl[4,5] with diisopropylamine or 2,2,6,6-tetramethylpiperidine (TMPH), respectively, in THF (−20° C.-80° C., for 0.1-48 h). The resulting Li/Mg-reagents 5a (R1 and R2=i-Pr) and 5b (R1R2N=2,2,6,6-tetramethylpiperidyl) proved to have an excellent solubility in THF (0.6 M and 1.2 M, respectively) as well as an improved kinetic acidity and regioselectivity for the magnesation of various aromatics and heterocycles.
- An overview over the increased selectivity and selectivity can be seen from Scheme 1a below. Here, the same substrates were reacted with a mono amide and a bisamide, and the yields of the respective reactions is given in the scheme. The base indicated above the reaction arrow in the scheme is the corresponding amide indicated in the right column of the scheme.
- The activity of the amides (I) can be shown on the basis of the magnesiation of isoquinoline. Diisopropylamido magnesium chloride-lithium chloride 5a leads to the magnesiated isoquinoline 6 after 12 h reaction time at 25° C. and by using 2 equivalents of the base. After iodolysis, the iodoisoquinoline 7a is isolated in 88% yield (Scheme 2). Even more active is the sterically more hindered and less aggregated 2,2,6,6-tetramethylpiperidino magnesium chloride-lithium chloride reagent 5b. It leads to a complete magnesiation within 2 h at 25° C. Remarkably, with this base only 1.1 equivalents are required to achieve a complete metalation. The resulting Grignard reagent 6 provides after iodolysis the iodoisoquinoline 7a in 96% yield (Scheme 2 and Table 1).
- After the magnesation of a reagent, it can be subjected to a transmetalation. After e.g. a transmetalation with CuCN.2LiCl (20 mol %), the addition of benzoyl chloride (1.2 equiv.) provides the ketone 7b in 86% yield (entry 2 of Table 1).
- The presence of an excess of magnesium amides often hampers the performance of palladium-catalyzed cross-couplings. The inventors found that the Grignard reagents generated by deprotonation with 5b (1.1 equiv.) such as 6 are readily transmetalated to the corresponding zinc derivative (ZnCl2 (1.1 equiv.), 0° C., 5 min.) and undergo a Negishi-cross-coupling reaction using Pd(dba)2 (5 mol %) (dba=dibenzylideneacetone), P(2-fur)3 (7 mol %) (fur=furyl) with ethyl 4-iodobenzoate (1.2 equiv.; 50° C., 12 h) leading to the arylated quinoline (7c) in 82% yield. This behaviour is general and 3-bromoquinoline is metalated with 5b (1.1 equiv., −30° C., 0.5 h) leading to the 2-magnesiated quinoline 8 (entries 4 and 5 of Table 1). Thus, the quenching of 8 with I2 and N,N-dimethylformamide (DMF) provides the two quinolines 9a and 9b in 96-93% yield.
- Whereas the deprotonation of 2,6-dichloropyridine with i-Pr2NMgCl.LiCl 5a and lithium diisopropylamide (LDA)[8j] provides a 1:1 mixture of 3- and 4-magnesiated 2,6-dichloro-pyridine, the use of TMPMgCl.LiCl 5b furnishes only the 4-magnesiated pyridine 10. Its reaction with typical electrophiles (I2, DMF and PhCHO) provides the expected products 11a-c in 84-93% yield (entries 6-8 of Table 1). Interestingly, metalation of 3,5-dibromopyridine with LDA proceeds selectively at 4-position[6b] while in the case of (TMPMgCl.LiCl 5b 1.1 equiv, −20° C., 0.5 h) regioselective metalation of 3,5-dibromopyridine is observed leading after the reaction with DMF to the pyridylaldehyde 13 in 95% yield (entry 9 of Table 1).
- The magnesiation of heterocycles bearing more acidic protons[7] such as thiazole, thiophene, furan, benzothiophene or benzothiazole proceeds smoothly between 0° C. and 25° C. leading to the organomagnesium derivatives 14a-c and 16a-b. After trapping with standard electrophiles, the expected products 15a-c and 17a-b are obtained in 81-98% yield (entries 10-14 of Table 1).
- The metalation of pyrimidine derivatives is a challenging problem due to the propensity of these heterocycles to add organometallic reagents.[8] The inventors found that the inverse addition of the pyrimidine derivatives 18-20 to a THF solution of 5b (1.05 equiv.) at −55° C. for approx. 5 min. provides the corresponding magnesiated derivatives 21-23 in 83-90% yields as indicated by iodolysis experiments leading to the iodinated pyrimidines 24-26 (scheme 3).
- The mixed magnesium-lithium amide 5b is also well suited for the regioselective metalation of polyfunctional aromatic systems. Thus, the reaction of 2-phenylpyridine 27 in THF at 55° C. with 5b (2.0 equiv.) for 24 h provides the Grignard reagent 28 showing a rare case where a phenyl ring is preferentially metalated compared to a pyridine ring. After iodolysis, the ortho-iodinated product 29 is obtained in 80% yield. Interestingly, the metalation of polyfunctional aromatics such as the bromodiester 30 also succeeds using only the stoichiometric amount of base 5b (1.1 equiv.) in THF (−30° C., 0.5 h) leading regioselectively to the arylmagnesium species 31 which after iodolysis furnishes the polyfunctional aromatic derivative 32 in 88% yield.
- A solution of TMPMgCl.LiCl can easily be prepared in THF due to its excellent solubility and it is stable for more than 6 months at 25° C. The use of TMPMgCl.LiCl allows for the regioselective functionalization of various aromatics and heteroaromatics. It gives access to new magnesium species not readily available via a Br/Mg-exchange reactions or by previously reported metalation procedures.
- The residues R1 and R2 are not limited to organic compounds. R1 and R2 may also be silylated compounds like trimethylsilyl. The preparation of the bis(trimethylsilyl) amide 33 can be achieved by reacting bis(trimethylsilyl)amine with i-PrMgCl.LiCl at room temperature (see Scheme 5). This base can efficiently be used to deprotonate ketones like e.g. cyclohexanone as can be seen from Scheme 5.
- The Grignard reagents can also be used to prepare a polymeric base. 2,2,6,6-Tetramethyl piperidine (TMPH) is a well known base. It can be used to prepare the corresponding mixed Mg/Li amide TMPMgCl.LiCl 5b. This monomeric base is very reactive but also very expensive. A corresponding polymeric base to TMPH is chimassorb 994, the structure of which is shown in Scheme 6.
- Chimassorb 994 can be used to prepare the corresponding mixed Mg/Li amide by reacting chimassorb 994 with i-PrMgCl.LiCl at room temperature (see Scheme 5). This base 34 is stable and soluble in THF before and after deprotonation. As being a polymeric base, it can be easily removed after completion of the reaction. Since chimassorb 994 is much cheaper than TMP, a corresponding base can be prepared at reduced costs. The polymeric base 34 shows slightly lower activity than monomeric TMPMgCl.LiCl but is nevertheless very effective in deprotonating compounds with acidic protons like isoquinoline. A corresponding example is shown in Scheme 7. The polymeric base can be used to deprotonate various substrates. For example, isoquinoline reacts at room temperature with the base 34 affording after quenching with iodine 1-iodoisoquinoline 7a.
- The above given examples show that the new mixed Mg/Li-bases of the general type R1R2NMgX.zLiY have a high kinetic activity due to the presence of a lithium salt which breaks oligomeric aggregates of magnesium amides.
- An example of a symmetrical bisamide reagent is (TMP)2Mg.2LiCl 40a. It is prepared by reacting in situ generated MgCl2 with lithium 2,2,6,6-tetramethylpiperidide (TMPLi) in THF at 0° C. for 30 minutes (see Scheme 8).
- Additionally, other symmetrical bisamides can be prepared in high yields using the same methodology as for the preparation of 40a. All examples shown below (40b-40c) were prepared in >95% yield (Scheme 9) in analogy to the preparation of 40a. This also includes bisamides containing silyl substituted amines.
- Comparative metalation experiments on aromatic substrates were performed under identical conditions with 1.1 equivalents of both (TMP)2Mg.2LiCl (40a) and TMPMgCl.LiCl (5b). The bisamide reagent (TMP)2Mg.2LiCl shows highly superior reactivity than TMPMgCl.LiCl and it was even able to deprotonate very weak acidic substrates.
- Scheme 10 gives an overview over examples of reactions of four different aromatic substances (41-44) with (TMP)2Mg.2LiCl (40a) and TMPMgCl.LiCl (5b) under identical conditions. The respective yields are indicated for the products of each of the two amides 40a and 5b. This experiment clearly shows the even superior reactivity of the bisamides in view of the monoamides. All reactions are carried out at room temperature (rt) being at 25° C.
- Additionally, the resultant Grignard intermediates derived from (TMP)2Mg.2LiCl show good stability and tolerance to various substrates. Furthermore, they react with different eletrophiles providing the corresponding functionalized derivatives in good yields. Examples are shown in Table 2 below.
- It could also be shown that mixed magnesium bases bearing two different amide functions, i.e. R1R2N and R3R4N being different, have improved properties over the corresponding symmetrical reagents bearing two identical amide functions. The unsymmetrical reagents 40e-40i are prepared from TMPMgCl.LiCl, i-Pr2NMgCl.LiCl and (2-ethyl-hexyl)2NMgCl.LiCl[9], respectively, and the corresponding lithium species of 1H-benzotriazole (Bt), 5,6-dimethyl-1H-benzotriazole (DMBt) and carbazole (CBZ), respectively (Scheme 11).
- Especially, the base 40e provides a far higher reactivity than TMPMgCl.LiCl (5b) and (TMP)2Mg.2LiCl (40a) when using special directing metalation groups (DMG). TMPMgCl.LiCl provides full metalation of 44 in 90 minutes at 0° C., and reagent 40a provides full metalation in 60 minutes. In contrast thereto, the use of 40e provides full metalation at 0° C. in only 10 minutes. Furthermore, only 1.3 equivalents of the base 40e are used in contrast to 1.5 equivalents of TMPMgCl.LiCl. Moreover, the yield of 44a is higher compared to the use of TMPMgCl.LiCl (Scheme 12).
- The regulating intermediates derived from (TMP)Mg(Bt).2LiCl show good stability and tolerance to various substrates. They can be trapped with an electrophile like iodine to provide the corresponding functionalized derivatives in good yields. Examples are shown in Table 3.
- The compounds of the present invention can also be used in connection with a phosphorodiamidate group on an aryl or heteroaryl. This effect will be shown in the following with the N,N,N′,N′-tetramethylphosphorodiamidate ((Me2N)2P(O)O—) group, but is not limited to this specific group. As a person skilled in the art will recognize immediately, other directing metalation groups can also be used, especially other phosphorodiamidate groups.
- Ortho-directed metalation is an important method for the functionalization of various aromatics and heterocycles. Various DMG (directed metalation groups) have been used for achieving efficient lithiations. The DMG allow for a fast and ortho-selective metalation mainly by chelation (entropic effect). Polar DMG may furthermore transfer electron density to the metal base and increase their metalating power. Recently, magnesiate bases have proven to be of great structural and synthetic interest for the functionalization of aromatics.
- As was shown above, mixed Li, Mg-bases like TMP2Mg.2LiCl are highly active and soluble magnesium bases allowing for smooth metalations of various aromatics and heterocycles with an excellent functional group compatibility. Surprisingly, the inventors found that the DMG N,N,N′,N′ tetramethylphosphorodiamidate ((Me2N)2P(O)O—) is a very strong directing group for magnesiation an it may overrule the effect of other substituents present in the aromatic substrate. In contrast to directed lithiations, which have usually to be performed at −105° C. to avoid Fries-type rearrangements, the magnesiation with TMP2Mg.2LiCl takes place (even at 0° C.) without anionic migration of the tetramethylphosphorodiamidate group. This would allow new types of functionalization such as formal meta- or para-functionalization (Scheme 13).
- Thus, the inventors have found that a range of aromatic phosphorodiamidates bearing either a functional group (FG) in the para-position (type 60) or in the meta-position (type 61) undergo an efficient magnesiation with TMP2Mg.2LiCl (40a) leading respectively to the products of type 62 and 63 after the addition of an electrophile. Substitution of the OP(O)(NMe2)2 group with a nucleophile (Nu) gives meta, para- and para, meta-difunctionalized molecules of type 64 and 65 as described below (Scheme 13 and Table 4). The magnesiation of substrates 61 and 62 using TMP2Mg.2LiCl (40a) proceeds smoothly within a few hours at 0° C. for cyano- and ester-substituted phosphorodiamidates 60a and 61a (entries 1-3, 10-13).
- For halogen-substituted starting materials (60b, 60c and 60d; entries 4-9) as well as for the trifluoromethyl-substituted phosphorodiamidate 61b (entry 14), lower temperatures (−40 to −50° C.) led to optimum results. In general, the regioselectivity of the metalation of aromatics is governed by a combination of electronic and/or sterical effects. However, the tetramethylphosphorodiamidate group is one of the strongest donor in organic synthesis and activates the Mg—N bond giving to the base an ate character (Scheme 14).
- This electronic effect increases the metalation power of the base and no additional chelation or inductive effects are necessary for achieving the magnesiation. Normally, this phosphorodiamidate-triggered magnesiation preferentially occurs at the sterically less hindered position of the aromatic ring promoting formal meta-metalation. However, in the case of meta-substituted substrates bearing bromo, chloro and fluoro as one of the functional groups, the inventors observed that the regioselectivity of the metalation is affected by the competitive directing effects of these halogens. Various electrophiles such as acid chlorides, TsCN, allylic halides, aldehydes or aromatic iodides react with the magnesium organometallic intermediates providing the desired products in 72-90% yields (Table 4). In the case of allylation and acylation reactions, the best results were obtained when the arylmagnesium species were transmetalated with ZnCl2 (1.2 equiv) and CuCN.2LiCl (0.5-1.3 equiv) prior to the addition of the acid chloride, TsCN or the allylic halide (entries 2-4,7,8 and 12).
- Similarly, Negishi cross-couplings with aryl iodides in the presence of Pd(dba)2 (2 mol %) and P(2-fur)3 (4 mol %) were successfully performed after transmetalation of the Grignard-reagents with ZnCl2 (entries 1, 5, 6 and 13). A double functionalization in meta, meta′-positions has also been achieved. Thus, the treatment of the nitrile 60a with TMP2Mg.2LiCl (1.1 equiv, 0° C., 4 h) followed by a copper(I)-catalyzed reaction with t-BuCOCl provides the ketone 62a in 81% yield. By applying the same reaction sequence (metalation at −60° C. for 0.5 h), the ketone 62a was converted to the diketone 66a in 77% yield. Furthermore, the double functionalization of the bromo- and chloro-substituted phosphorodiamidates 60b and 60d led to the preparation of the highly functionalized phosphorodiamidates 66b and 66c in good overall yields, showing the high directing power of the OP(O)(NMe2)2 group (Scheme 15).
- The further manipulation of the functionalized aryl phosphorodiamidates of type 62 and 63 was best achieved by converting these intermediates into derived fluorinated sulfonates such as nonaflates or triflates. Thus, a microwave assisted deprotection of aryl phosphorodiamidates 62b and 62c with formic acid in aqueous ethanol (120° C., 30 min) provides polyfunctional phenols, which after the reaction with C4F9SO2F (NaH, Et2O, 25° C., 12 h) allowed the isolation of the corresponding nonaflates 67a and 67b in 71% yield (Scheme 4). A nickel-catalyzed cross-coupling of nonaflate 67a with the arylzinc reagent 69 afforded the biphenyl 68a in 90% yield. On the other hand, reaction of 67b with dimethylamine-borane complex in the presence of catalytic amount of Pd(PPh3)4 gave the reduced derivative 68b in 94% yield. Similarly, the aryl phosphorodiamidate 63b was successfully converted to the diester 68c and to the ketoester 68d in 74% and 95% yield respectively, showing that this reaction sequence allows either efficient functionalization or removal of the directing metalation group (Scheme 16).
- In summary, this approach allows to achieve new functionalization pattern of aromatics by performing magnesiations using the powerful TMP2Mg.2LiCl base (40a) combined with the phosphorodiamidate (—OP(O)(NMe2)2) as strong directing metalation group. This methodology allows a general preparation of various meta-, para- and meta, meta′-polyfunctionalized aromatics which are not easily accessible by using conventional synthetic strategies. Applications toward the synthesis of biologically active molecules seem to be feasible with this approach.
- As can be seen from the above given examples, the new mixed Mg/Li-bases are very effective in deprotonating organic compounds. The deprotonation can be achieved in different solvents and can preferably be conducted at temperatures between −90° C. and 100° C. Further, due to the effective deprotonation reaction, the amides of the present invention preferably only require the use of 0.9-5 equivalents, more preferably 1-2 equivalents and most preferably 1.1-1.5 equivalents per proton to be deprotonated.
- With this new type of base, which is highly soluble and the side products of which do not disturb the following reactions, many new products may be obtained, or known reactions pathways will be more efficient. A person skilled in the art will easily recognise the benefit of the new Mg/Li-base and will be able to use this base in a wide variety of chemical reactions.
- In the following, examples are given to illustrate the present invention. However, these examples are given for illustrative purposes only and are not supposed to limit the scope of the invention which is determined by the claims below.
- A dry and argon flushed 250 mL flask, equipped with a magnetic stirrer and a septum, was charged with freshly titrated i-PrMgCl.LiCl (100 mL, 1.2 M in THF, 120 mmol). 2,2,6,6-tetramethylpiperidine (TMPH) (19.8 g, 126 mmol, 1.05 equiv) was added dropwise at room temperature. The reaction mixture was stirred until gas evaluation was completed (ca. 24 h) at room temperature.
- A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with TMPMgCl.LiCl (5 mL, 1.2 M in THF, 6.0 mmol). Isoquinoline (703 mg, 5.45 mmol) in THF (5 ml) was added dropwise at room temperature. During addition, the reaction mixture became red and the metalation was complete after 2 h (as checked by GC analysis of reaction aliquots quenched with a solution of I2 in THF, the conversion was more than 98%). A solution of I2 in THF (6 ml, 1 M in THF, 6.0 mmol) was slowly added at −20° C. The reaction mixture was quenched with sat. aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with ether (4×10 mL), dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by filter column chromatography (CH2Cl2/pentane) yielding 1-iodoisoquinoline (7a; 1.33 mg, 96%) as slightly yellow crystals (mp=74-76° C.).
- The products listed in table 1 below can be produced according to the preparation of 1-iodoisoquinoline (7a).
-
TABLE 1 Products obtained by the magnesiation of heterocycles with TMPMgCl•LiCl (5b) and reaction with electrophiles. Magnesium T, t Yield Entry reagent[a] [° C., h][b] Electophile Product (%)[c] 1 25, 2 I2 96 2 6 25, PhCOCl[d] 7b: R = COPh 86 2 3 6 25, 2 7c: R = 4-EtO2C6H4 82 4 −30, 0.5 I2 96 5 8 −30, DMF 9b: R = CHO 93 0.5 6 25, 0.1 I2 93 7 10 25, DMF 11b: R = CHO 90 0.1 8 10 25, PhCHO 11c: R = CH(OH)Ph 84 0.1 9 −25, 0.5 DMF 95 10 25, 24 DMF 81 11 14b: X = S, 25, DMF 15b: R = CHO 90 Y = CH 24 12 14c: X = S, 0, PhCHO 15c: R = CH(OH)Ph 94 Y = N 0.1 13 25, 24 DMF 93 14 16b: X = S, 0, I2 17b: R = I 98 Y = N 0.1 [a]Lithium chloride and TMPH are complexed to the Grignard reagent. [b]Reaction conditions for the deprotonation with TMPMgCl•LiCl (5b, 1.1 equiv.). [c]Isolated yield of analytically pure product. [d]A transmetalation with CuCN•2LiCl (0.2 equiv) was performed - Magnesium turnings (15 mmol) were placed in an argon-flushed-Schlenk flask and THF (30 ml) was added. 1,2-Dichloroethane (16 mmol) was added dropwise and the reaction was stirred until all magnesium was consumed, approximately 2 h. In another argon-flushed-Schlenk flask 2,2,6,6-tetramethylpiperidine (TMPH) (30 mmol) and THF (20 ml) were placed. This solution was cooled to −40° C. and n-BuLi (30 mmol) was added dropwise. After the addition, the reaction mixture was warmed to 0° C. and stirred at same temperature for 30 min. The MgCl2 solution was then transferred via cannula into the TMPLi solution and the reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for an additional 1 h. The solvents were removed then in vacuo followed by addition of THF while stirring until complete dissolution of the salts. The fresh (TMP)2Mg.2LiCl solution was titrated prior to use at 0° C. against benzoic acid using 4-(phenylazo)-diphenylamine as indicator.Average concentration in THF was 0.6 mol/1.
- Prepared according to 40a from pyrrolidine (PIR) (30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) in THF. Average concentration in THF was found to be 0.65 mol/l.
- Prepared according to 40a from diisopropylamine (30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) in THF. Average concentration in THF was found to be 0.84 mol/1.
- Prepared according to 40a from 1,1,1,3,3,3-hexamethyldisilazane (HMDS) (30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) in THF. Average concentration in THF was found to be 0.86 mol/L.
- Benzotriazole (Bt)(1.19 g, 10.0 mmol) was placed in a flame dried, argon flushed 50 ml Schlenk tube equipped with magnetic stirring bar and septum. THF (10 ml) was added. The solution was cooled to −40° C. Then n-BuLi (3.62 ml, 2.76 M in hexane, 10.0 mmol) was added drop wise. White precipitate was formed immediately. After the end of the addition the resulting suspension was stirred at −40° C. for 30 min. Then solvents were removed in vacuo followed by addition of TMPMgCl.LiCl (8.93 ml, 1.12 M in THF, 10.0 mmol). After the complete dissolving of the white solid, THF was removed in vacuo. To the resulting brownish gel, THF was added while stirring until complete dissolution of the salts. The fresh (TMP)Mg(Bt).2LiCl solution was titrated at room temperature against benzoic acid using 4-(phenylazo)-diphenylamine as an indicator. Average concentration in THF was found to be 0.35 mol/1.
- Prepared according to 40e from 5,6-dimethyl-1H-benzotriazole (10 mmol), n-BuLi (10 mmol) and TMPMgCl.LiCl (10 mmol) in THF. Average concentration in THF was found to be 0.33 mol/l.
- Prepared according to 40e from 9H-carbazole (10 mmol), n-BuLi (10 mmol), TMPMgCl.LiCl (10 mmol) in THF. Average concentration in THF was found to be 0.33 mol/l.
- Prepared according to 40e from benzotriazole (10 mmol), n-BuLi (10 mmol) and (i-Pr2N)MgCl.LiCl (10 mmol) in THF. Average concentration in THF was found to be 0.24 mol/1.
- Prepared according to 40e from benzotriazole (10 mmol), n-BuLi (10 mmol) and (2-ethyl-hexyl)2NMgCl.LiCl (10 mmol) in THF. Average concentration in THF was found to be 0.23 mol/l.
- Prepared according to 40a from iso-propyl(tert-butyl)amine (30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) in THF. Average concentration in THF was found to be 0.80 mol/L.
- Prepared according to 40a from iso-propyl(cyclo-hexyl)amine (30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) in THF. Average concentration in THF was found to be 0.60 mol/L
- A dry and nitrogen-flushed 10-ml-Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with a solution of the di-tert-butyl isophthalate (278 mg, 1 mmol) in dry THF (1 ml). After cooling to 0° C., a freshly prepared (TMP)21Mg.2LiCl solution (0.6 mol/l in THF, 1.83 ml, 1.1 mmol) was added dropwise and the reaction mixture was stirred at the same temperature. The completion of the metalation (2 h) was checked by GC-analysis of reaction aliquots quenched with a solution of I2 in dry ether. Iodine (508 mg, 2 mmol) dissolved in dry THF (2 ml) was then added at 0° C. and the resulting mixture warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with sat. aq. Na2S2O3, extracted with ether (3×20 ml) and dried over Na2SO4. After filtration the solvent was removed in vacuo. Purification by flash-chromatography (n-pentane/diethyl ether, 10:1) furnished compound Ma (380 mg, 94%) as a yellow oil.
- The products listed in Table 2 below can be produced according to the preparation of di-tert-butyl 4-iodobenzene-1,3-dioate (51a), using the corresponding temperatures and reactions times as indicated in the table.
-
TABLE 2 Products obtained by the magnesiation of aromatics with (TMP)2Mg•2LiC1 and reactions with eletrophiles. Entry Substrate Temp. [° C.] Time Electrophile E+ Product Yield 1 25 1 h PhCOCla 93% 2 41 25 1 h p-IPhCO2Etb 41c: E = p-PhCO2Et 82% 3 −10 1 h I2 71% 4 53 −10 1 h PhCOCla 53b: E = COPh 52% 5 25 1 h I2 78% 6 45 25 1 h EtCOCla 45b: E = COEt 7% 7 0 2 h I2 6% 8 47: X = Br −20 3 h I2 47a: E = I 74% 9 −20 4 h I2 91% 10 48 −20 4 h PhCOCla 48b: E = PhCO 62% 11 0 5 h BrCl2C2Cl2Br 60% 12 −40 5 h I2 77% 13 49 −40 5 h BrCl2C2Cl2Br 49b: = Br 70% 14 −40 12 h I2 66% 15 25 2 h I2 94% aA transmetalation with CuCN•2LiCl was performed. bObtained by palladium-catalyzed cross-coupling after transmetalation with ZnCl2. - A dry and nitrogen-flushed 25-ml Schlenk flask, equipped with a magnetic stirring bar and a septum, was charged ethyl 3-{[bis(dimethylamino)phosphoryl]oxy}benzoate 44 (300 mg, 1.00 mmol) in dry THF (3 ml). After cooling to 0° C., a freshly prepared (TMP)Mg(Bt).2LiCl solution (4.33 ml, 0.3 M in THF, 1.3 mmol) was added dropwise and the reaction mixture was stirred at the same temperature. The completion of the metalation (10 min) was checked by GC-analysis of reaction aliquots quenched with a solution of I2 in dry THF. Iodine (508 mg, 2.0 mmol) dissolved in dry THF (2 ml) was then added at 0° C. and the resulting mixture warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with sat. aq. Na2S2O3, extracted with ether (3×20 ml) and dried over Na2SO4. After filtration, the solvent was removed in vacuo. Purification by flash-chromatography using ethyl acetate as eluent furnished ethyl 3-{[(bis(dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a (332 mg, 78%) as a yellow oil.
- The products listed in Table 3 below can be produced according to the preparation of ethyl 3-{[b is (dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a, using the corresponding temperatures and reactions times as indicated in the table.
- In a dry argon-flushed Schlenk-tube, 2,2,6,6-tetramethylpiperidine (TMPH; 5.07 mL, 30 mmol) was dissolved in THF (30 mL). This solution was cooled to −40° C., and n-BuLi (2.4 in hexane, 12.5 mL, 30 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0° C. and stirred at this temperature for 30 min. Freshly titrated TMPMgCl.LiCl (5b) (1 M in THF, 30 mL, 30 mmol) was then added dropwise to the LiTMP-solution, the reaction mixture was stirred at 0° C. for 30 min, warmed to 25° C. and stirred for 1 h. The solvents were then removed in vacuo without heating, affording a yellowish solid. Freshly distilled THF was slowly added under vigorous stirring, until a complete dissolution of the salts was observed. The fresh TMP2Mg.2LiCl solution was titrated prior to use at 0° C. with benzoic acid using 4-(phenylazo)-diphenylamine as indicator. A concentration of 0.6 M in THF was obtained.
- In a dry argon-flushed Schlenk-tube the aryl phosphorodiamidate 60d (2.62 g, 8.00 mmol) was dissolved in THF (8 mL), cooled to −40° C. and TMP2Mg.2LiCl (0.6 M in THF, 14.7 mL, 8.8 mmol) was added dropwise. The mixture was stirred at −40° C. for 1.5 h. Complete metalation was detected by GC-analysis of reaction aliquots which were quenched with I2 in dry THF. A solution of ZnCl2 (1 M in THF, 9.6 mL, 9.6 mmol) was added dropwise, and the resulting mixture stirred for 15 min. A solution of Pd(dba)2 (88 mg, 2 mol %) and P(2-fur)3 (72 mg, 4 mol %) in THF (8 mL) was added, followed by 4-iodoanisole (2.06 g, 8.8 mmol) and the reaction mixture was allowed to warm to room temperature. After stirring for 12 h, the reaction mixture was quenched with aq. sat. NH4Cl solution (20 mL) and extracted with diethyl ether (3×50 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate) furnished 62c (2.78 g, 90% yield) as an orange oil.
-
TABLE 4 Products of type 62 and 63 obtained by direct magnesiation of the aromatic phosphoroamidates 60 and 61 with (TMP)2Mg•2LiCl (2) followed by the reaction with electrophiles (E-X). T [° C.], Yield Entry Substrate t [h] E-X Product [%]a 1 0, 1 p-IC6H4OTIPS 83c 2 60a 0, TsCN 62e: E = CN 77b 1 3 60a 0, CH2═C(CH3)CH2Br 62f: E = CH2═C(CH3)CH2 84b 1 4 −50, 7 tBuCH2COCl 72b 5 −40, 4 p-IC6H4CO2Et 78c 6 60c −40, m-Tol-I 62i: E = m-Tol 75c 4 7 60c −40, c-C6H9Br 62j: E = c-C6H9 85b 4 8 −40, 1.5 PhCOCl 85b 9 60d −40, tBuCHO 62l: E = tBuC(OH) 79 1.5 10 0, 1 (BrCl2C)2 80 12 61a 0, PhCOCl 63b: E = COPh 73b 1 13 61a 0, p-IC6H4CO2Et 63c: E = p-C6H4CO2Et 78c 1 14 −40, 2 I2 88 15 0, 0.5 (BrCl2C)2 76 aIsolated yield of analytically pure product. bA transmetalation with ZnCl2 (1.1 equiv) and CuCN•2LiCl (0.5-1.3 equiv) was performed. cObtained by a palladium-catalyzed cross-coupling after transmetalation with ZnCl2 (1.1 equiv). -
- [1] a) M. Schlosser, Angew. Chem. Int. Ed, 2005, 44, 376-393. b) A. Turck, N. Ple, F. Mongin, G. Queguiner, Tetrahedron 2001, 57, 4489-4505. c) F. Mongin, G. Qúeguiner, Tetrahedron 2001, 57, 4059-4090 d) M. Schlosser, Eur. J. Org. Chem. 2001, 21, 3975-3984. e) D. M. Hodgson, C. D. Bray, N. D. Kindon, Org. Lett. 2005, 7, 2305-2308. f) J-C. Plaquevent, T. Perrard, D. Cahard, Chem. Eur. J. 2002, 8, 3300-3307. g) C.-C. Chang, M. S. Ameerunisha, Coord. Chem. Rev. 1999, 189, 199-278. h) J. Clayden, Organolithiums: Selectivity for Synthesis. Editor(s): J. E. Baldwin, R. M. Williams 2002, Publisher: Elsevier. i) F. Leroux, M. Schlosser, E. Zohar, I. Marek, The preparation of organolithium reagents and intermediates Editor(s): Rappoport, Zvi; Marek, Ilan. Chemistry of Organolithium Compounds 2004, 1, 435-493. Publisher: John Wiley & Sons Ltd. j) K. W. Henderson, W. J. Kerr, Chem.-A Ear. J. 2001, 7(16), 3430-3437. k) K. W. Henderson, W. J. Kerr, J. H. Moir, Tetrahedron 2002, 58(23), 4573-4587. l) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed. 2004, 43(17), 2206-2225. m) G. Queguiner, F. Marsais, V. Snieckus, J. Epsztajn, Adv. in Het. Chem. 1991, 52, 187-304. n) M. Veith, S. Wieczorek, K. Fries, V. Huch, Z. Anorg. Allg. Chem. 2000, 626(5), 1237-1245.
- [2] a) M-X. Zhang, P. E. Eaton, Angew. Chem. Int. Ed. 2002, 41, 2169-2171. b) Y. Kondo, Y. Akihiro, T. Sakamoto, J. Chem. Soc., Perkin Trans. 1: Org. Bio-Org. Chem. 1996, 19, 2331-2332. c) P. E. Eaton, C. H. Lee, Y. Xiong, J. Am. Chem. Soc. 1989, 111, 8016-18. d) P. E. Eaton, M-X. Zhang, N. Komiya, C-G. Yang, I. Steele, R. Gilardi, Synlett 2003, 9, 1275-1278. e) P. E. Eaton, R. M. Martin, J. Org. Chem. 1988, 53, 2728-32. f) M. Shilai, Y. Kondo, T. Sakamoto, J. Chem. Soc., Perkin Trans. 1: Org. Bio-Org. Chem. 2001, 4, 442. g) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. 2003, 115, 4438-4456.
- [3] a) Y. Kondo, M. Shilai, M. Uchiyama, T. Sakamoto, J. Am. Chem. Soc. 1999, 121, 3539-3540. b) T. Imahori, M. Uchiyama, T. Sakamoto, Y. Kondo, Chem. Comm. 2001, 23, 2450-2451.
- [4] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 4438; Angew. Chem. Int. Ed. 2004, 43, 3333. b) H. Ren, A. Krasovskiy, P. Knochel, Chem. Commun. 2005, 543. c) H. Ren, A. Krasovskiy, P. Knochel, Org. Lett. 2004, 6, 4215.
- [5] i-PrMgCl.LiCl is commercially available from Chemetall GmbH (Frankfurt)
- [6] a) A. 3. Clarke, S. McNamara, O. Meth-Cohn, Tetrahedron Lett. 1974, 27, 2373-6. b) Y. G. Gu; E. K. Bayburt, Tetrahedron Lett. 1996, 37, 2565.
- [7] a) H. Froehlich, W. Kalt, J. Org. Chem. 1990, 55, 2993-5. b) C. Peyron, J-M. Navarre, N. Van Craynest, R. Benhida, Tetrahedron Lett. 2005, 46, 3315-3318. c) D. W. Slocum, P. L. Gierer, J. Org. Chem. 1976, 41, 3668-74.
- [8] a) Y. G. Gu, E. K. Bayburt, Tetrahedron Lett. 1996, 37, 2565-8. b) W. Schlecker, A. Huth, E. Ottow, J. Mulzer, Lieb. Ann. 1995, 8, 1441-6. c) W. Schlecker, A. Huth, E. Ottow, J. Mulzer, J. Org. Chem. 1995, 60, 8414-16. d) A. Bouillon, J-C. Lancelot, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2002, 58, 3323-3328. e) A. Bouillon, J-C. Lancelot, J. S. de O, Santos, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2003, 59, 10043-10049. f) A. Bouillon, J-C. Lancelot, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2002, 58, 4369-4373. g) A. Bouillon, J-C, Lancelot, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2002, 58, 2885-2890. h) H. Awad, F. Mongin, F. Trecourt, G. Queguiner, F. Marsais, Tetrahedron Lett. 2004, 45, 7873-7877. i) D. L. Comins, M. O. Killpack, J. Org. Chem. 1990, 55, 69-73. j) R. Radinov, Kh. Chanev, M. Khaimova, J. Org. Chem. 1991, 56, 4793-6. k) S. Choppin, P. Gros, Y. Fort, Org. Lett. 2000, 2, 803-805.
- [9] (2-Ethyl-hexyl)2NMgCl.LiCl is prepared by reacting bis(2-ethylhexyl)amine with i-Pr2NMgCl.LiCl in THF at room temperature for 48 h. For a general procedure see A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 2958-2961.
Claims (29)
1. A reagent of the general formula
R1R2N—Mg—NR3R4 .zLiY (II)
R1R2N—Mg—NR3R4 .zLiY (II)
wherein
R1, R2, R3, and R4 are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silyl derivatives thereof; and R1 and R2 together, or R3 and R4 together can be part of a cyclic or polymeric structure; and wherein at least one of R1 and R2 and at least one of R3 and R4 is other than H;
Y is selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalOn, wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO3; BF4; PF6; H; a carboxylate of the general formula RXCO2; an alcoholate of the general formula ORX; a thiolate of the general formula SRX; RXP(O)O2; or SCORX; or SCSRX; OnSRX, wherein n=2 or 3; or NOR, wherein n=2 or 3; and a derivative thereof; wherein RX is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, or H; and
z>1;
or as adduct with a solvent.
2. Solution of the reagent according to claim 1 in a solvent.
3. Solution according to claim 2 , wherein the solvent is selected from cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes, triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide; cyclic amides, cyclic, linear or branched alkanes and/or alkenes wherein one or more hydrogens are replaced by a halogen, urea derivatives, aromatic, heteroaromatic or aliphatic hydrocarbons, hexamethylphosphorus triamide (HMPA), CS2; or combinations thereof.
4. Solution according to claim 3 , wherein the solvent is 1,4-dioxane.
5. Solution according to claim 3 , wherein the solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
6. Solution according to claim 3 , wherein the solvent is N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), and/or N-butyl-2-pyrrolidone (NBP).
7. Solution according to claim 3 , wherein the solvent is N,N′-dimethylpropyleneurea (DMPU).
8. Solution according to claim 3 , wherein the solvent is dichloromethane, 1,2-dichloroethane, and/or CCl4.
9. Solution according to claim 3 , wherein the solvent is benzene, toluene, xylene, pyridine, pentane, cyclohexane, hexane, and/or heptane.
10. Use of the reagent according to claim 1 in a reaction with an electrophile.
11. Use of the reagent according to claim 1 for the deprotonation of any substrate which can form stabilized or unstabilized carbaniones.
12. Process for the preparation of a mixed Mg/Li amide comprising reacting in a solvent a primary or secondary amine with a Grignard reagent in the presence of a lithium salt, or with a Grignard reagent complexed with a lithium salt, or reacting in a solvent a primary or secondary lithium amide with a magnesium salt.
13. Process for the preparation of a reagent having the general formula
R1R2N—Mg—NR3R4 .zLiY (II)
R1R2N—Mg—NR3R4 .zLiY (II)
wherein
R1, R2, R3, and R4 are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silicon derivatives thereof; and R1 and R2 together, or R3 and R4 together can be part of a cyclic or polymeric structure; and wherein at least one of R1 and R2 and at least one of R3 and R4 is other than H;
Y is selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalOn, wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO3; BF4; PF6; H; a carboxylate of the general formula RXCO2; an alcoholate of the general formula ORX; a thiolate of the general formula SRX; RXP(O)O2; or SCORX; or SCSRX; OnSRX wherein n=2 or 3; or NOn wherein n=2 or 3; and a derivative thereof; wherein Rx is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, or H; and
z>1;
comprising
reacting in a solvent R1R2N—MgX or R1R2N—MgX.zLiY with R3R4NLi, or reacting R1R2NLi and R3R4NLi with MgX2; and
X is defined as Y above.
14. Process according to claim 13 , wherein X and Y are independently or both Cl, Br or I.
15. Process according to claim 14 , wherein X and Y are independently or both Cl.
16. Process according to claim 13 , wherein z is in the range from 1-5.
17. Process according to claim 16 , wherein z is in the range from 1.5-2.5.
18. Process according to claim 16 , wherein z is in the range from 1.8-2.2.
19. Process according to claim 16 , wherein z is in the range from 1.9-2.1.
20. Process according to claim 16 , wherein z is in the range from 1.95-2.05.
21. Process according to claim 16 , wherein z is about 2.
22. Process according to claim 13 , wherein the Grignard reagent R′MgX.zLiY is iPrMgCl.LiCl.
23. Process according to claim 13 , wherein the solvent is selected from cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes, triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide; cyclic amides; cyclic, linear or branched alkanes and/or alkenes wherein one or more hydrogens are replaced by a halogen; urea derivatives; aromatic, heteroaromatic or aliphatic hydrocarbons; hexamethylphosphorus triamide (HMPA), CS2; or combinations thereof.
24. Process according to claim 13 , wherein the solvent is 1,4-dioxane.
25. Process according to claim 13 , wherein the solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
26. Process according to claim 13 , wherein the solvent is N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), and/or N-butyl-2-pyrrolidone (NBP).
27. Process according to claim 13 , wherein the solvent is N,N′-dimethylpropyleneurea (DMPU).
28. Process according to claim 13 , wherein the solvent is benzene, toluene, xylene, pyridine, pentane, cyclohexane, hexane, and/or heptane.
29. Process according to claim 13 , wherein the solvent is dichloromethane, 1,2-dichloroethane, and/or CCl4.
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JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine/Piperazine derivatives |
EP2297101B1 (en) * | 2008-05-21 | 2016-07-13 | Chemetall GmbH | Method for manufacturing magnesium amides |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002689A (en) * | 1988-02-25 | 1991-03-26 | Lithium Corporation Of America | Preparation of organometallic amide compositions |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4944894A (en) * | 1988-02-25 | 1990-07-31 | Lithium Corporatoin Of America | Ether free organometallic amide compositions |
EP0282419B1 (en) * | 1987-03-13 | 1995-04-05 | Lithium Corporation Of America | Ether free organometallic amide compositions |
US5300252A (en) * | 1987-03-13 | 1994-04-05 | Fmc Corporation | Ether free organometallic amide compositions |
US5359105A (en) * | 1993-11-01 | 1994-10-25 | Albemarle Corporation | Deprotonation of cyclopentadienyl derivatives |
US5610227A (en) * | 1995-06-07 | 1997-03-11 | Bridgestone/Firestone, Inc. | Lithium amino magnesiate polymerization initiators and elastomers having reduced hysteresis |
EP1582523A1 (en) * | 2004-04-02 | 2005-10-05 | Ludwig-Maximilians-Universität München | Method of preparing organomagnesium compounds |
EP1810974A1 (en) | 2006-01-18 | 2007-07-25 | Ludwig-Maximilians-Universität München | Preparation and use of magnesium amides |
-
2006
- 2006-01-18 EP EP06001017A patent/EP1810974A1/en not_active Withdrawn
-
2007
- 2007-01-18 AT AT07703987T patent/ATE512156T1/en active
- 2007-01-18 EP EP07703987A patent/EP1981893B1/en active Active
- 2007-01-18 WO PCT/EP2007/050492 patent/WO2007082911A1/en active Application Filing
- 2007-01-18 US US12/087,351 patent/US8134005B2/en active Active
- 2007-01-18 ES ES11166878.6T patent/ES2605239T3/en active Active
- 2007-01-18 EP EP11166878.6A patent/EP2360161B1/en active Active
- 2007-01-18 CN CN2007800024216A patent/CN101370815B/en active Active
- 2007-01-18 ES ES07703987T patent/ES2369973T3/en active Active
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- 2008-01-04 CN CN200880002287A patent/CN101622260A/en active Pending
- 2008-01-04 WO PCT/EP2008/050066 patent/WO2008087057A1/en active Application Filing
- 2008-01-04 JP JP2009545884A patent/JP2010516649A/en not_active Withdrawn
- 2008-01-04 US US12/522,494 patent/US20100144516A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002689A (en) * | 1988-02-25 | 1991-03-26 | Lithium Corporation Of America | Preparation of organometallic amide compositions |
US5320774A (en) * | 1988-02-25 | 1994-06-14 | Fmc Corporation | Preparation of organometallic amide compositions |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100160632A1 (en) * | 2007-05-14 | 2010-06-24 | Ludwig Maximilians Universitat Munchen | Bisamid-zinkbasen |
US8513416B2 (en) | 2007-05-14 | 2013-08-20 | Ludwig-Maximilians-Universitat Muenchen | Bisamide-zinc bases |
US9273070B2 (en) | 2010-12-22 | 2016-03-01 | Paul Knochel | Organozinc complexes and processes for making and using the same |
Also Published As
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CN101370815B (en) | 2012-05-23 |
ES2369973T3 (en) | 2011-12-09 |
ATE512156T1 (en) | 2011-06-15 |
WO2007082911A1 (en) | 2007-07-26 |
EP1810974A1 (en) | 2007-07-25 |
EP1981893B1 (en) | 2011-06-08 |
US20090176988A1 (en) | 2009-07-09 |
JP5638758B2 (en) | 2014-12-10 |
CN101622260A (en) | 2010-01-06 |
EP2360161A1 (en) | 2011-08-24 |
US8134005B2 (en) | 2012-03-13 |
CN101370815A (en) | 2009-02-18 |
ES2605239T3 (en) | 2017-03-13 |
WO2008087057A1 (en) | 2008-07-24 |
JP2009523765A (en) | 2009-06-25 |
EP2360161B1 (en) | 2016-08-31 |
JP2010516649A (en) | 2010-05-20 |
EP1981893A1 (en) | 2008-10-22 |
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