CN111212824A - 酮的定向β-C(sp3)-H碘化和芳基化 - Google Patents
酮的定向β-C(sp3)-H碘化和芳基化 Download PDFInfo
- Publication number
- CN111212824A CN111212824A CN201880066562.2A CN201880066562A CN111212824A CN 111212824 A CN111212824 A CN 111212824A CN 201880066562 A CN201880066562 A CN 201880066562A CN 111212824 A CN111212824 A CN 111212824A
- Authority
- CN
- China
- Prior art keywords
- nmr
- cdcl
- 150mhz
- hrms
- tof
- 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.)
- Granted
Links
- 150000002576 ketones Chemical class 0.000 title claims abstract description 44
- 238000006192 iodination reaction Methods 0.000 title claims description 55
- 238000006254 arylation reaction Methods 0.000 title claims description 12
- 230000026045 iodination Effects 0.000 title description 46
- 238000000034 method Methods 0.000 claims abstract description 64
- NQRKYASMKDDGHT-UHFFFAOYSA-N (aminooxy)acetic acid Chemical compound NOCC(O)=O NQRKYASMKDDGHT-UHFFFAOYSA-N 0.000 claims abstract description 17
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 claims abstract description 15
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002923 oximes Chemical class 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 9
- 125000003544 oxime group Chemical group 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- XMOTUEBORAJQFR-UHFFFAOYSA-N 2,2-bis(methylaminooxy)acetic acid Chemical compound CNOC(C(=O)O)ONC XMOTUEBORAJQFR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001503 aryl iodides Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 4
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 3
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 2
- 230000001052 transient effect Effects 0.000 abstract description 9
- 238000004587 chromatography analysis Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000009434 installation Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 207
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 239000000758 substrate Substances 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 51
- 238000012746 preparative thin layer chromatography Methods 0.000 description 36
- -1 oxime carboxylic acid Chemical class 0.000 description 35
- 239000003480 eluent Substances 0.000 description 34
- 238000000746 purification Methods 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- 239000000203 mixture Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000012230 colorless oil Substances 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000007306 functionalization reaction Methods 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000003780 insertion Methods 0.000 description 5
- 230000037431 insertion Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KBXIJIPYZKPDRU-UHFFFAOYSA-N (aminooxy)acetic acid hemihydrochloride Chemical compound Cl.NOCC(O)=O.NOCC(O)=O KBXIJIPYZKPDRU-UHFFFAOYSA-N 0.000 description 2
- HMWSNSPVDVXJPA-RVDMUPIBSA-N 2-[(E)-(3,3-dimethyl-4-phenylbutan-2-ylidene)amino]oxyacetic acid Chemical compound CC(\C(\C)=N\OCC(=O)O)(CC1=CC=CC=C1)C HMWSNSPVDVXJPA-RVDMUPIBSA-N 0.000 description 2
- ZYAIGJHDDOOPEE-FOWTUZBSSA-N 2-[(E)-(3-benzyl-3-methylpentan-2-ylidene)amino]oxyacetic acid Chemical compound C(C1=CC=CC=C1)C(\C(\C)=N\OCC(=O)O)(CC)C ZYAIGJHDDOOPEE-FOWTUZBSSA-N 0.000 description 2
- RNCVAUOQTCYJHV-FMIVXFBMSA-N 2-[(E)-1-(1-methylcyclohexyl)ethylideneamino]oxyacetic acid Chemical compound CC1(CCCCC1)\C(\C)=N\OCC(=O)O RNCVAUOQTCYJHV-FMIVXFBMSA-N 0.000 description 2
- JFLDNZBRDHRCFQ-JXMROGBWSA-N 2-[(E)-3,3-dimethylpentan-2-ylideneamino]oxyacetic acid Chemical compound CC(\C(\C)=N\OCC(=O)O)(CC)C JFLDNZBRDHRCFQ-JXMROGBWSA-N 0.000 description 2
- ROMJJCRSCLAWGQ-ZIEJOHADSA-N 2-[(E)-[(1S,4R)-1,3,3-trimethyl-2-bicyclo[2.2.1]heptanylidene]amino]oxyacetic acid Chemical compound C[C@]12/C(/C([C@H](CC1)C2)(C)C)=N\OCC(=O)O ROMJJCRSCLAWGQ-ZIEJOHADSA-N 0.000 description 2
- KPZWPICEYTUOIC-FVTBZGPOSA-N 2-[(E)-[(E)-4,4-dimethyl-1-phenylpent-1-en-3-ylidene]amino]oxyacetic acid Chemical compound CC(/C(/C=C/C1=CC=CC=C1)=N/OCC(=O)O)(C)C KPZWPICEYTUOIC-FVTBZGPOSA-N 0.000 description 2
- OCUYHSCLZJGZOL-XDJHFCHBSA-N 2-[(E)-[6-(2,5-dimethylphenoxy)-3,3-dimethylhexan-2-ylidene]amino]oxyacetic acid Chemical compound CC1=C(OCCCC(\C(\C)=N\OCC(=O)O)(C)C)C=C(C=C1)C OCUYHSCLZJGZOL-XDJHFCHBSA-N 0.000 description 2
- SEULHZJZJGYWLX-FYWRMAATSA-N 2-[(Z)-[1-(4-methoxyphenyl)-2,2-dimethylpropylidene]amino]oxyacetic acid Chemical compound COC1=CC=C(C=C1)\C(\C(C)(C)C)=N/OCC(=O)O SEULHZJZJGYWLX-FYWRMAATSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- VTRILNKMRNAVCG-XBFLQQSZSA-N CC(/C(=N/OCC(=O)O)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)C.CC(/C(=N/OCC(=O)O)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)C Chemical compound CC(/C(=N/OCC(=O)O)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)C.CC(/C(=N/OCC(=O)O)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)C VTRILNKMRNAVCG-XBFLQQSZSA-N 0.000 description 2
- LHXDLQBQYFFVNW-UHFFFAOYSA-N Fenchone Chemical compound C1CC2(C)C(=O)C(C)(C)C1C2 LHXDLQBQYFFVNW-UHFFFAOYSA-N 0.000 description 2
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- PNBFPTRVPMOUFP-XQNSMLJCSA-N ethyl (3E)-3-[2-(3,5-dimethylanilino)-2-oxoethoxy]imino-5-iodo-4-(iodomethyl)-4-methylpentanoate Chemical compound CC=1C=C(C=C(C=1)C)NC(CO\N=C(/CC(=O)OCC)\C(CI)(C)CI)=O PNBFPTRVPMOUFP-XQNSMLJCSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960003627 gemfibrozil Drugs 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- AIEFWPONAXOMOR-UHFFFAOYSA-N iodomethyl butanoate Chemical compound CCCC(=O)OCI AIEFWPONAXOMOR-UHFFFAOYSA-N 0.000 description 2
- DWMALLSZKWFLBJ-OQKWZONESA-N methyl 2-[(E)-[2-[tert-butyl(dimethyl)silyl]oxy-3-iodo-2-(iodomethyl)-1-phenylpropylidene]amino]oxyacetate Chemical compound ICC(/C(=N/OCC(=O)OC)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)CI DWMALLSZKWFLBJ-OQKWZONESA-N 0.000 description 2
- MHZFCCDRMCSHNL-UHFFFAOYSA-N methyl 2-[[3-benzyl-4-iodo-3-(iodomethyl)butan-2-ylidene]amino]oxyacetate Chemical compound COC(=O)CON=C(C)C(CI)(CI)Cc1ccccc1 MHZFCCDRMCSHNL-UHFFFAOYSA-N 0.000 description 2
- WNZSMLFUICKILB-UHFFFAOYSA-N methyl 4-[4-(1-methoxy-2-methyl-1-oxopropan-2-yl)oxyiminopentan-2-yl]benzoate Chemical compound COC(C(C)(C)ON=C(CC(C)C1=CC=C(C(=O)OC)C=C1)C)=O WNZSMLFUICKILB-UHFFFAOYSA-N 0.000 description 2
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- LHXDLQBQYFFVNW-XCBNKYQSSA-N (+)-Fenchone Natural products C1C[C@]2(C)C(=O)C(C)(C)[C@H]1C2 LHXDLQBQYFFVNW-XCBNKYQSSA-N 0.000 description 1
- HFXAUXXNFFAIMD-YRNVUSSQSA-N 2-[(E)-(1-cyano-3,3-dimethylbutan-2-ylidene)amino]oxyacetic acid Chemical compound C(#N)C/C(/C(C)(C)C)=N\OCC(=O)O HFXAUXXNFFAIMD-YRNVUSSQSA-N 0.000 description 1
- JLYSHFVOOFVJBL-WYMLVPIESA-N 2-[(Z)-(2,2-dimethyl-1-phenylpropylidene)amino]oxyacetic acid Chemical compound CC(/C(/C1=CC=CC=C1)=N/OCC(=O)O)(C)C JLYSHFVOOFVJBL-WYMLVPIESA-N 0.000 description 1
- SMULPWDFVAAHBU-RMKNXTFCSA-N 2-[(e)-3,3-dimethylbutan-2-ylideneamino]oxyacetic acid Chemical compound CC(C)(C)C(/C)=N/OCC(O)=O SMULPWDFVAAHBU-RMKNXTFCSA-N 0.000 description 1
- XAUAXBRVDRZZHE-UHFFFAOYSA-N 3-ethyl-3-(iodomethyl)-5-phenylpentan-2-one Chemical compound C(C)C(C(C)=O)(CCC1=CC=CC=C1)CI XAUAXBRVDRZZHE-UHFFFAOYSA-N 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- AWRRDLZGUMWGNG-UHFFFAOYSA-N ICC1(CCCCC1)C=C Chemical group ICC1(CCCCC1)C=C AWRRDLZGUMWGNG-UHFFFAOYSA-N 0.000 description 1
- 239000012696 Pd precursors Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000006137 acetoxylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- RVIQSSNDHKQZHH-UHFFFAOYSA-N carbonyl diiodide Chemical compound IC(I)=O RVIQSSNDHKQZHH-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AOPYTYIOWZRBOS-KGENOOAVSA-N ethyl (3E)-3-[2-(3,5-dimethylanilino)-2-oxoethoxy]imino-2-(iodomethyl)-2-methylbutanoate Chemical compound CC=1C=C(C=C(C=1)C)NC(CO\N=C(\C(C(=O)OCC)(C)CI)/C)=O AOPYTYIOWZRBOS-KGENOOAVSA-N 0.000 description 1
- ZTKKVMDVNIJBQZ-CJLVFECKSA-N ethyl (3E)-3-[2-(3,5-dimethylanilino)-2-oxoethoxy]imino-5-iodo-4,4-dimethylpentanoate Chemical compound CC=1C=C(C=C(C=1)C)NC(CO\N=C(/CC(=O)OCC)\C(CI)(C)C)=O ZTKKVMDVNIJBQZ-CJLVFECKSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229930006735 fenchone Natural products 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- IWPIBYAIIANFKF-HEHNFIMWSA-N methyl 2-[(E)-[2-[tert-butyl(dimethyl)silyl]oxy-3-iodo-2-methyl-1-phenylpropylidene]amino]oxyacetate Chemical compound ICC(/C(=N/OCC(=O)OC)/C1=CC=CC=C1)(O[Si](C(C)(C)C)(C)C)C IWPIBYAIIANFKF-HEHNFIMWSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0213—Complexes without C-metal linkages
- B01J2531/0219—Bimetallic complexes, i.e. comprising one or more units of two metals, with metal-metal bonds but no all-metal (M)n rings, e.g. Cr2(OAc)4
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
- C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了通过使用可商购获得的氨基氧乙酸助剂,钯(II)催化的广泛的酮的β‑C(sp3)‑H碘化或芳基化的第一实施例。该L,X型导向基团克服了瞬态导向基团方法对酮的β‑C(sp3)‑H官能化的限制。该方法的实际优势包括无需色谱法即可简便地安装助剂,对α‑官能团的超强耐受性、双键和三键以及可快速访问各种空间受阻的季中心。
Description
相关申请的交叉引用
本申请要求2017年8月16日提交的美国临时申请序列号62/546,166的优先权,其公开内容通过引用全部并入本文。
政府支持声明
本发明是利用在国立普通医学科学院(the National Institutes of GeneralMedical Sciences)授予的授权号GM084019下的政府支持完成的。政府拥有本发明的某些权利。
背景技术
酮在有机化学中无处不在,其可用作宝贵的散装化学品、合成组成部分和天然产物。尽管已经在不对称烯醇化学中广泛研究了α-酸性C-H键的反应性,1但惰性β-C(sp3)-H键的直接官能化可通过提供新的合成断开基团进一步扩展酮的合成效用。尽管自从Shaw、Sutherland、Baldwin等人的开创性工作以来,已经报道了化学计量的肟定向的β-C(sp3)-H钯化反应(palladation)以及随后的乙酰氧基化和碘化反应,2但是相应的催化反应的发展在范围和效率方面仍然受到限制,尽管最近有了进展。3-5最近,使用催化瞬态氨基酸导向基团还实现了酮的β-C(sp3)-H芳基化反应。6然而,由于自由瞬态导向基团经常干扰偶联剂和催化剂,因此该策略与许多合成上理想的转化方法不兼容。与羧酸和胺的β-C(sp3)-H官能化相比,使用共价或瞬态导向基团进行的酮的β-C(sp3)-H官能化在底物范围和转化方面都受到很大限制。7
发明内容
在多种实施方案中,本发明涉及经由Pd(II)催化的反应的具有β-氢取代基的酮的β-取代方法,例如β-碘化和β-芳基化。该方法采用由氨基氧乙酸形成的酮的肟作为导向基团,然后分别与碘或与芳基碘化物接触。然后例如在酸性条件下,通过裂解辅助肟基团将所得到的β-取代的肟转化为β-取代的酮。
更具体地说,本发明可以提供一种具有β-氢取代基的酮的β-C(sp3)-H碘化的方法,其包括:
使所述酮和氨基氧乙酸在吡啶溶剂中接触以提供相应的肟;
然后,
在非质子溶剂中,在钯(II)盐和乙酸苯碘铵的存在下使所述肟与碘接触;
然后,
在酸性条件下水解所述肟基团,以提供所述产物β-C(sp3)-碘酮。
例如,所述氨基氧乙酸可以是氨基氧乙酸或2,2-二甲基氨基氧乙酸。例如,所述钯(II)盐可以是乙酸钯(II)或三氟乙酸钯(II)。例如,所述非质子溶剂可以是二噁烷或1,1,1,3,3,3-六氟异丙醇。例如,所述肟基团可以在浓盐酸的二噁烷溶液中水解。
此外,本发明可以提供一种具有β-氢取代基的酮的β-C(sp3)-H芳基化方法,其包括:
使所述酮和氨基氧乙酸在吡啶溶剂中接触以提供所述相应的肟;
然后,
在非质子溶剂中在钯(II)盐存在下使所述肟与芳基碘化物和三氟乙酸银接触;然后,
在酸性条件下水解所述肟基团,以提供所述产物β-C(sp3)-芳基酮。
例如,所述氨基氧乙酸可以是氨基氧乙酸或2,2-二甲基氨基氧乙酸。例如,所述钯(II)盐可以是乙酸钯(II)或三氟乙酸钯(II)。例如,所述非质子溶剂可以是二噁烷或1,1,1,3,3,3-六氟异丙醇。例如,所述肟基团在浓盐酸的二噁烷溶液中水解。
尽管已经对本发明进行了足够详细的描述和例示,以使本领域技术人员能够制造和使用本发明,但是在不脱离权利要求的精神和范围的情况下,各种替代方案、修改方案和改进方案对于本领域技术人员而言将是显而易见的。
具体实施方式
在此,我们报告了一种实际的导向基团,该基团使得能够进行酮的β-碘化和β-芳基化。在我们先前的瞬态导向基团中建立的亚氨基羧酸螯合与肟键的稳定性相结合成功克服了先前导向基团的局限性,推测产生了高活性的Pd前体。因此,本文报道的底物范围比以前报道的酮的C(sp3)-H官能化要宽得多。
从逐步经济的角度来看,将氨基酸瞬态导向基团用于酮的β-C(sp3)-H官能化具有吸引力。然而,所使用的游离氨基酸通常与多种氧化剂或偶联剂不相容,从而阻止了多种转化的发展。由于已显示双齿亚氨基-羧基螯合可有效指导C(sp3)-H活化,6我们建议用更稳定的肟8基序取代亚胺以使键不可逆(方案1)。
方案1.基于氨基酸的瞬时和共价导向基团
瞬态DG:限于芳基化
共价DG:具有优越的范围的新的转化
重要的是,如方案2所示,L,X型(即中性、阴离子)导向基团比L,L(即中性、中性)对应基团具有根本优势。使用L,L型导向基团,C-H键必须置换乙酸根,以形成热力学不利的阳离子Pd(II)物质,以便实现CH插入。(方案2,方程2)。
此外,与其他高度稳定的双齿配合物相比,羧酸的弱配位性质也有利于C-H插入中间体的反应性。
方案2.有功效的导向基团的合理设计
为了测试该设计原理,我们出于两个理由选择β-C(sp3)-H碘化作为模型反应:首先,酮的C(sp3)-H碘化除了由Sutherland在1984年报道的肟的化学计量的碘加成反应的单个示例外,仍然是一个未解决的问题。2b其次,β-碘酮是极为通用的合成子,然而,β-碘酮的合成是众所周知的挑战,特别是对于空间受阻的α-季酮。9因此,模型底物1a-1可在温和的条件下通过松果油酮与可商购获得的氨基氧乙酸之间的缩合反应以高收率轻松制得,无需色谱法。在我们先前对羧酸底物的噁唑啉和酸性酰胺定向的β-C(sp3)-H碘化的研究的指导下,5,10我们发现用1当量(equiv)的I2、PhI(OAc)2和10mol%Pd(OAc)2的1,4-二噁烷溶液以70%的收率得到所需的碘化产物。使用其他溶剂会明显降低收率。用Pd(TFA)2代替Pd(OAc)2可使收率提高至88%(表1)。
表1.C(sp3)-H碘化的导向基团评估a,b,c
a条件:底物(0.1mmol,1.0当量)、Pd(TFA)2(10mol%)、I2(1.0当量)、PhI(OAc)2(1.0当量)、1,4-二噁烷(1.25mL),40℃,在空气中,20小时。Ar1=4-CF3(C6F4),Ar1=3,5-CH3(C6H3)。b使用CH2Br2作为内标,通过1H NMR分析粗产物确定收率。c括号中的数字表示单:双(mono:di)或单:双:三(mono:di:tri)的比例(如果适用)。dPd(TFA)2(5mol%)。
重要的是,将催化剂负载量降低至5mol%不会导致收率的显著降低。观察到的高反应性促使我们研究导向基团的配位方式以及结构对反应性的影响。带有甲基酯的相应的L,L型导向基团(DG2)产生低收率,这证实了L,X型辅助剂的优越性(方案2,方程1-2)。加强二齿的配位作用(由于Thorp-Ingold效应)导致二碘化和三碘化产物(2a-3)急剧增加,这很可能是由于与Pd的解离缓慢所致。考虑到酸性酰胺导向基团的公认效率,11我们还将羧酸转化为酰胺(DG4和DG5)。尽管DG4具有可比的反应性,但较强的结合亲和力导致主要形成三碘化产物。如所预期的那样,酸性较低的酰胺DG5的反应性不强,大概是由于其无法采用L,X型配位。
通过确定最佳的导向基团和反应条件,我们评估了C(sp3)-H碘化的范围。值得强调的是该导向基团的实际优势:使用可商购获得的氨基氧乙酸无需色谱法即可进行多种底物的制备。如表2所示,多种烷基取代的酮以良好至优异的收率被β-碘化(2a-d)。请注意,产品2a-c和2e-h中的季中心无法通过经典的烯醇化烷基化方法来达到,因为α-甲基的烷基化在动力学上是有利的;1所有这些产品均以良好至优异的收率形成。尽管存在三个α-甲基,但双环天然产物Fenchone仍然以优异的单选择性碘化(2d)。值得注意的是,与羧基导向部分反式连接的芳族部分与碘化条件相容,并且未检测到C(sp2)-H碘化(2e-g,2o)。衍生自吉非贝齐(Gemfibrozil)的酮在β-甲基和芳环上被碘化(2h)。在碘化反应期间,与羧基导向部分顺式连接的各种芳环保持完整(2i-k,2p-r)。值得注意的是,在酸性α-氢存在下没有观察到α-碘化,12仅获得了β-C(sp3)-H碘化产物(2k-m)。同样,这些产品中的季铵盐中心不能使用烯醇盐烷基化反应形成,其优选酸性甚至更高且受阻较少的α-位。1最后,α-位的各种官能团(包括腈、酯、TBS保护的羟基、烯基和炔基)是耐受的(2l-r),从而显示出与以前报道的肟导向的C(sp3)-H官能化相比要宽得多的底物范围。
表2.酮的C(sp3)-H碘化a,b,c
a条件:底物(0.1mmol,1.0当量)、Pd(TFA)2(10mol%)、I2(1.0当量)、PhI(OAc)2(1.0当量)、1,4-二噁烷(1.25mL),40℃,在空气中,20小时。b分离收率。c括号中的数字表示单:双的比率。c参见后处理程序的示例,T1和T2。d反应时间为3小时。e反应温度为80℃。
与以前开发的亚胺导向基团相比,这种新的助剂提供许多实际优势。2-5最重要的是,与O-甲基肟导向基团相比,亚氨基-羧基导向基团显示出与含有苯基、应变环、烯烃和其他官能团的多种底物的优异的反应性(方案3)。
方案3.与O-甲基肟导向基团不相容的酮底物
由于亚胺键的不稳定性,先前用我们先前的瞬时氨基酸导向基团分离C-H插入中间体的尝试均未成功。通过更稳定的肟键,我们很高兴在80℃下通过搅拌底物1a和1.2当量的Pd(OAc)2在HFIP中的溶液观察到C-H插入中间体的形成。我们能够通过用PPh3捕获来分离稳定的复合物,收率为81%(方案4)。通过X射线晶体学确认该结构。该中间体为亚氨基-羧酸导向基团的L,X配位模式提供了第一直接证据,从而证实了羧基作为导向部分的独特作用。
方案4.钯环的表征
方案5.助剂的去除
碘化后,可以使用标准的酸水解技术裂解肟助剂,以便以良好的收率得到碘代酮产物。参见实施例部分。
总之,使用可商购获得的氨基氧乙酸助剂开发了酮的C(sp3)-H碘化反应。该反应的特点是易于安装和去除助剂。底物的范围比先前报道的使用各种方法进行的酮的C-H官能化要宽得多。C-H插入中间体的特征也为亚胺-羧酸导向基团的L,X型配位模式提供了第一直接证据。
酮的C(sp3)-H芳基化
新的肟导向基团也可用于通过类似途径形成β-芳基酮。形成肟之后,在三氟乙酸银的存在下于六氟异丙醇中与Pd(II)盐反应并与芳基碘化物偶合,然后像以前一样处理所得的芳基化产物,形成肟羧酸的甲基酯。如上所述进行肟的裂解以产生β-芳基化的酮。
引用文件
(1)Cano,R.;Zakarian,A.;McGlacken,G.P.Angew.Chem.,Int.Ed.2017,DOI:10.1002/anie.201703079.
(2)对于化学计量的钯化反应的选定示例:(a)Constable,A.G.;McDonald,W.S.;Sawkins,L.C.;Shaw,B.L.J.Chem.Soc.Chem,Commun.1978,1061.(b)Carr,K.;Sutherland,J.K.J.Chem.Soc.Chem,Commun.1984,1227.(c)Baldwin,J.E.;Nájera,C.;Yus,M.J.Chem.Soc.Chem,Commun.1985,126.(d)Baldwin,J.E.;Jones,R.H.;Nájera,C.;Yus,M.Tetrahedron 1985,41,699.
(3)对于Pd催化的C(sp2-)-H卤代反应的早期示例:(a)Fahey,D.R.J.Organomet.Chem.1971,27,283.(b)Andrienko,O.S.;Goncharov,V.S.;Raida,V.S.Russ.J.Org.Chem.1996,32,89.
(4)对于通过使用肟导向基团的催化的C(sp3)-H活化的进展:(a)Desai,L.V.;Hull,K.L.;Sanford,M.S.J.Am.Chem.Soc.2004,126,9542.(b)Thu,H.-Y.;Yu,W.-Y.;Che,C.-M.J.Am.Chem.Soc.2006,128,9048.(c)Kang,T.;Kim,Y.;Lee,D.;Wang,Z.;Chang,S.J.Am.Chem.Soc.2014,136,4141.(d)Gao,P.;Guo,W.;Xue,J.;Zhao,Y.;Yuan,Y.;Xia,Y.;Shi,Z.J.Am.Chem.Soc.2015,137,12231.
(5)对于由手性噁唑啉导向的不对称C(sp3-)-H碘化反应:Giri,R.;Chen,X.;Yu.J.-Q.Angew.Chem.,Int.Ed.2005,44,2112.
(6)(a)Zhang,F.-L.;Hong,K.;Li,T.-J.;Park,H.;Yu,J.-Q.Science 2016,351,252.(b)Yang,K.;Li,Q.;Liu,Y.;Li,G.;Ge,H.J.Am.Chem.Soc.2016,138,12775.
(7)对于Pd催化的C(sp3)-H官能化的选定综述:(a)Daugulis,O.;Do,H.-Q.;Shabashov,D.Acc.Chem.Res.2009,42,1074.(b)Lyons,T.W.;Sanford,M.S.Chem.Rev.2010,110,1147.(c)He,J.;Wasa,M.;Chan,K.S.L.;Shao,Q.;Yu,J.-Q.Chem.Rev.2017,DOI:10.1021/acs.chemrev.6b00622.
(8)Kalia,J.;Raines,R.T.Angew.Chem.,Int.Ed.2008,47,7523.
(9)Roman,B.I.;Kimpe,N.D.;Stevens,C.V.Chem.Rev.2010,110,5914.
(10)对于酸性酰胺导向的C(sp3-)-H碘化:Zhu,R.-Y.;Saint-Denis,T.G.;Shao,Y.;He,J.;Sieber,J.D.;Senanayake,C.H.;Yu,J.-Q.J.Am.Chem.Soc.2017,139,5724.
(11)对于选定的示例:(a)Wasa,M.;Engle,K.M.;Yu,J.-Q.J.Am.Chem.Soc.2010,132,3680.(b)Wasa,M.;Chan,K.S.L.;Zhang,X.-G.;He,J.;Miura,M.;Yu,J.-Q.J.Am.Chem.Soc.2012,134,18570.(c)Li,S.;Chen,G.;Feng,C.-G.;Gong,W.;Yu,J.-Q.J.Am.Chem.Soc.2014,136,5267.(d)Zhu,R.-Y.;He,J.;Wang,X.-C.;Yu,J.-Q.J.Am.Chem.Soc.2014,136,13194.(e)Zhu,R.-Y.;Tanaka,K.;Li,G.-C.;He,J.;Fu,H.-Y.;Li,S.-H.;Yu,J.-Q.J.Am.Chem.Soc.2015,137,7067.(f)Wu,Q.-F.;Shen,P.-X.;He,J.;Wang,X.-B.;Zhang,F.;Shao,Q.;Zhu,R.-Y.;Mapelli,C.;Qiao,J.X.;Poss,M.A.;Yu,J.-Q.Science 2017,355,499.
(12)对于酮的α-碘化反应的选定示例:(a)Bekaert,A.;Barberan,O.;Gervais,M.;Brion,J.-D.Tetrahedron Lett.2000,41,2903.(b)Jereb,M.;Stavber,S.;Zupan,M.Synthesis 2003,853.(c)Wang,Z.;Yin,G.;Qin,J.;Gao,M.;Cao,L.;Wu,A.Synt hesis2008,3565.
实施例
一般信息
酮从商业来源获得或按照文献程序合成,并用于制备相应的底物。氨基氧乙酸半盐酸盐获自Combi-Blocks。I2从TCI获得。PhI(OAc)2从Sigma-Aldrich获得。溶剂获自Sigma-Aldrich、Alfa-Aesar和Acros,并且无需进一步纯化即可直接使用。分析薄层色谱法在0.25mm硅胶60-F254上进行。可视化是使用UV光和Vogel的高锰酸盐进行的。在Bruker AMX-400仪器(400MHz)或Bruker DRX-600仪器(600MHz)上记录1H NMR。化学位移以百万分之一(ppm)表示,相对于四甲基硅烷为0.0ppm。以下缩写(或它们的组合)用于解释多重性:s=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰,br=宽峰。耦合常数J以赫兹单位(Hz)表示。13C NMR光谱记录在Bruker AMX-400仪器(100MHz)或Bruker DRX-600仪器(150MHz)上,并通过宽带质子解耦而完全解耦。19F NMR光谱记录在Bruker AMX-400仪器(100MHz)上,并通过宽带质子解耦而完全解耦。相对于氯仿-d为77.0ppm的三重峰中心线或丙酮-d为29.84ppm的多重峰中心线,以ppm为单位报道了化学位移6。在13C NMR分析中,与聚氟芳基酰胺助剂的峰对应的峰显示为几乎不可见的复杂的成组的多重峰;在下面的光谱分析中将它们省略。使用ESI-TOF(电喷雾电离-飞行时间)在安捷伦质谱仪(Agilent Massspectrometer)上记录了高分辨率质谱(HRMS)。
底物结构
实验部分
底物制备
用于底物1a、1b、1d、1i、1l、1m和1p的酮是可商购获得的。按照文献程序合成底物1e、1f和1g的酮。1通过相应的羧酸与MeLi之间的反应合成用于底物1c和1h的酮。该程序可在文献中找到。2按照文献程序合成用于底物1j的酮。3按照文献程序合成用于底物1k的酮。2按照文献程序合成用于底物1n和1o的酮。4按照文献程序合成用于底物1q的酮。5按照文献程序合成用于底物1r的酮。6
在空气下将酮(2mmol,1当量)和氨基氧乙酸半盐酸盐(4mmol,437mg,2当量)称重到在具有磁力搅拌棒经烘箱干燥的50mL圆底烧瓶中。加入5mL吡啶,并将混合物在60℃下搅拌2h。完成后,大部分吡啶在真空下蒸发。所得混合物用EtOAc(50mL)稀释,并依次用水(100mL)和稀HCl水溶液(100mL,约0.01M)洗涤。有机相用无水Na2SO4干燥,并在真空下除去溶剂。值得注意的是,在所有情况下均以高收率获得纯化合物而无需色谱法。
(E)-2-(((3,3-二甲基丁-2-亚基)氨基)氧基)乙酸)(1a)
1H NMR(600MHz,CDCl3)δ4.59(s,2H),1.90(s,3H),1.12(s,9H)。13C NMR(150MHz,CDCl3)δ174.41,166.90,69.93,37.30,27.44,10.88。HRMS(ESI-TOF)计算值C8H14NO3 -[M-H]-:172.0979,实测值:172.0972。
(E)-2-(((3,3-二甲基戊-2-亚基)氨基)氧基)乙酸(1b)
1H NMR(600MHz,CDCl3)δ4.58(s,2H),1.86(s,3H),1.47(q,J=7.2Hz,2H),1.08(s,6H),0.76(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ174.73,165.83,70.05,40.67,32.74,24.97,10.79,8.81。HRMS(ESI-TOF)计算值C9H16NO3 -[M-H]-:186.1136,实测值:186.1132。
(E)-2-(((1-(1-甲基环己基)亚乙基)氨基)氧基)乙酸(1c)
1H NMR(600MHz,CDCl3)δ4.60(s,2H),1.88(s,3H),1.82-1.79(m,2H),1.51-1.31(m,8H),1.07(s,3H)。13C NMR(150MHz,CDCl3)δ174.06,166.24,69.81,40.78,35.20,35.15,26.05,25.97,22.35。HRMS(ESI-TOF)计算值C11H18NO3 -[M-H]-:212.1292,实测值:212.1287。
2-(((E)-((1S,4R)-1,3,3-三甲基双环[2.2.1]庚-2-亚基)氨基)氧基)乙酸(1d)
按照一般程序合成1d,不同的是反应温度为120℃且反应时间为12小时。1H NMR(600MHz,CDCl3)δ4.51(s,2H),1.87-1.84(m,1H),1.81-1.78(m,1H),1.75-1.73(m,1H),1.61-1.59(m,2H),1.44-1.38(m,2H),1.30(s,3H),1.28(s,3H),1.21(s,3H)。13C NMR(150MHz,CDCl3)δ176.60,173.20,69.98,50.55,48.49,45.04,43.31,34.19,25.11,23.26,22.47,16.88。HRMS(ESI-TOF)计算值C12H18NO3 -[M-H]-:224.1292,实测值:224.1288。
(E)-2-(((3,3-二甲基-4-苯基丁-2-亚基)氨基)氧基)乙酸(1e)
1H NMR(600MHz,CDCl3)δ7.27-7.19(m,3H),7.06-7.04(m,2H),4.52(s,2H),2.74(s,2H),1.96(s,3H),1.09(s,6H)。13C NMR(150MHz,CDCl3)δ174.64,165.30,137.90,130.26,127.81,126.25,70.12,46.05,41.36,25.11,11.65。HRMS(ESI-TOF)计算值C14H18NO3 -[M-H]-:248.1292,实测值:248.1297。
(E)-2-(((3-苄基-3-甲基戊-2-亚基)氨基)氧基)乙酸(1f)
1H NMR(600MHz,CDCl3)δ7.26-7.23(m,2H),7.21-7.19(m,1H),7.05-7.04(m,2H),4.54(ABq,J=16.8Hz,2H),2.82(d,J=13.8Hz,1H),2.67(d,J=13.8Hz,1H),1.94(s,3H),1.71-1.65(m,1H),1.42-1.36(m,1H),0.99(s,3H),0.80(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ173.94,164.61,137.76,130.27,127.83,126.26,70.01,45.12,44.97,31.10,20.78,11.70,8.64。HRMS(ESI-TOF)计算值C15H20NO3 -[M-H]-:262.1449,实测值:262.1442。
(E)-2-(((3-乙基-3-甲基-5-苯基戊-2-亚基)氨基)氧基]乙酸(1g)
1H NMR(600MHz,CDCl3)δ7.28-7.25(m,2H),7.18-7.14(m,3H),4.63(s,2H),2.52(td,J=5.4Hz,J=13.2Hz,1H),2.38(td,J=4.8Hz,J=13.2Hz,1H),1.86(s,3H),1.83-1.78(m,1H),1.66-1.54(m,2H),1.47-1.41(m,1H),1.12(s,3H),0.78(t,J=7.2Hz,3H)。13CNMR(150MHz,CDCl3)δ174.43,164.66,142.62,128.36,128.25,125.73,69.89,44.07,41.00,31.70,30.77,20.68,10.89,8.38。HRMS(ESI-TOF)计算值C16H22NO3 -[M-H]-:276.1605,实测值:276.1609。
(E)-2-(((6-(2,5-二甲基苯氧基)-3,3-二甲基己-2-亚基)氨基)氧基)乙酸(1h)
1H NMR(600MHz,CDCl3)δ7.00(d,J=7.2Hz,1H),6.66(d,J=7.6Hz,1H),6.60(s,1H),4.60(s,2H),3.92-3.88(m,2H),2.30(s,3H),2.17(s,3H),1.90(s,3H),1.66-1.63(m,4H),1.14(s,6H)。13C NMR(150MHz,CDCl3)δ173.98,166.02,156.92,136.48,130.28,123.48,120.67,111.88,69.85,67.78,40.31,36.65,25.48,24.78,21.38,15.78,10.85。HRMS(ESI-TOF)计算值C18H26NO4 -[M-H]-:320.1867,实测值:320.1862。
(Z)-2-(((2,2-二甲基-1-苯基亚丙基)氨基)氧基)乙酸(1i)
1H NMR(600MHz,CDCl3)δ7.42-7.39(m,2H),7.37-7.34(m,1H),7.12-7.10(m,2H),4.51(s,2H),1.17(s,9H)。13C NMR(150MHz,CDCl3)δ174.65,168.26,127.91,127.90,127.35,127.34,70.23,37.48,28.16。HRMS(ESI-TOF)计算值C13H16NO3 -[M-H]-:234.1136,实测值:234.1130。
(Z)-2-(((1-(4-甲氧基苯基)-2,2-二甲基亚丙基)氨基)氧基)乙酸(1j)
1H NMR(600MHz,CDCl3)δ7.06-7.04(m,2H),6.95-6.92(m,2H),4.54(s,2H),3.82(s,3H),1.16(s,9H)。13C NMR(150MHz,CDCl3)δ174.14,168.57,159.15,128.59,125.62,113.47,70.04,55.14,37.71,28.17。HRMS(ESI-TOF)计算值C14H18NO4 -[M-H]-:262.1241,实测值:262.1247。
(E)-2-(((3,3-二甲基-1-苯基丁-2-亚基)氨基)氧基]乙酸(1k)
1H NMR(600MHz,CDCl3)δ7.28-7.25(m,2H),7.23-7.22(m,2H),7.19-7.17(m,1H),4.63(s,2H),3.81(s,2H),1.11(s,9H)。13C NMR(150MHz,CDCl3)δ174.94,167.09,136.77,128.43,128.25,126.08,69.95,37.81,31.80,28.13。HRMS(ESI-TOF)计算值C14H18NO3 -[M-H]-:248.1292,实测值:248.1299。
(E)-2-(((1-氰基-3,3-二甲基丁-2-亚基)氨基)氧基)乙酸(1l)
1H NMR(600MHz,CDCl3)δ4.75(s,2H),3.36(s,2H),1.19(s,9H)。13C NMR(150MHz,CDCl3)δ174.19,157.34,115.14,70.19,37.46,27.14,13.66。HRMS(ESI-TOF)计算值C9H13N2O3 -[M-H]-:197.0932,实测值:197.0939。
(E)-2-(((1-乙氧基-4,4-二甲基-1-氧戊-3-亚基)氨基)氧基)乙酸](1m)
1H NMR(600MHz,CDCl3)δ4.64(s,2H),4.21(q,J=7.2Hz,2H),3.42(s,2H),1.28(t,J=7.2Hz,3H),1.12(s,9H)。13C NMR(150MHz,CDCl3)δ172.06,170.18,162.19,70.92,62.10,37.31,31.53,26.96,13.97。HRMS(ESI-TOF)计算值C11H18NO5 -[M-H]-:244.1190,实测值:244.1185。
(E)-2-(((4-乙氧基-3,3-二甲基-4-氧丁-2-亚基)氨基)氧基]乙酸(1n)
1H NMR(400MHz,CDCl3)δ4.65(s,2H),4.16(q,J=7.2Hz,2H),1.89(s,3H),1.37(s,6H),1.24(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ174.70,174.20,161.35,70.02,61.17,48.95,23.04,14.02,12.46。HRMS(ESI-TOF)计算值C10H16NO5 -[M-H]-:230.1034,实测值:230.1030。
(E)-2-(((3-苄基-4-乙氧基-3-甲基-4-氧丁-2-亚基)氨基)氧基)乙酸(1o)
1H NMR(400MHz,CDCl3)δ7.24-7.20(m,3H),7.09-7.07(m,2H),4.63(s,2H),4.16(q,J=7.2Hz,2H),3.25(d,J=13.6Hz,1H),3.06(d,J=13.6Hz,1H),1.91(s,3H),1.26(s,3H),1.24(t,J=8.8Hz,3H)。13C NMR(150MHz,CDCl3)δ174.33,173.60,160.37,136.65,130.35,128.01,126.70,70.08,61.24,53.82,41.05,20.19,14.01,13.30。HRMS(ESI-TOF)计算值C16H20NO5 -[M-H]-:306.1347,实测值:306.1340。
(E)-6,6,8,8,9,9-六甲基-5-苯基-3,7-二氧杂-4-氮杂-8-硅癸-4-烯-1-酸((E)-6,6,8,8,9,9-hexamethyl-5-phenyl-3,7-dioxa-4-aza-8-siladec-4-en-1-oic acid)(1p)
1H NMR(600MHz,CDCl3)δ7.43-7.34(m,3H),7.26-7.24(m,2H),4.57(s,2H),1.48(s,6H),0.77(s,9H),0.02(s,6H)。13C NMR(150MHz,CDCl3)δ174.26,165.76,132.70,128.17,128.11,127.65,75.58,70.14,29.18,25.75,18.09,-2.16。HRMS(ESI-TOF)计算值C18H28NO4Si-[M-H]-:350.1793,实测值:350.1790。
2-(((E)-((E)-4,4-二甲基-1-苯基戊-1-烯-3-亚基)氨基)氧基)乙酸(1q)
1H NMR(600MHz,CDCl3)δ7.49-7.47(m,2H),7.42(d,J=16.8Hz,1H),7.38-7.35(m,2H),7.33-7.30(m,1H),6.64(d,J=16.8Hz,1H),4.67(s,2H),1.24(s,9H)。13C NMR(150MHz,CDCl3)δ173.28,163.69,139.88,136.47,128.93,128.74,127.00,116.29,70.31,37.70,28.63。HRMS(ESI-TOF)计算值C15H18NO3 -[M-H]-:260.1292,实测值:260.1299。
(Z)-2-(((4,4-二甲基-1-苯基戊-1-炔-3-亚基)氨基)氧基]乙酸(1r)
1H NMR(600MHz,CDCl3)δ7.54-7.52(m,2H),7.39-7.34(m,3H),4.72(s,2H),1.26(s,9H)。13C NMR(150MHz,CDCl3)δ173.92,152.03,132.13,129.51,128.40,121.70,101.73,78.71,70.52,37.39,28.06。HRMS(ESI-TOF)计算值C15H16NO3 -[M-H]-:258.1136,实测值:258.1132。
C(sp3)-H碘化
紫外线活性酮的C(sp3)-H碘化的一般程序:在空气下将底物1(0.10mmol)、Pd(TFA)2(0.01mmol,3.3mg)、I2(0.10mmol,25.4mg)和PhI(OAc)2(0.10mmol,32.2mg)称入具有磁力搅拌棒的反应瓶(10mL)中。加入1,4-二噁烷(1.25mL),并将小瓶用盖密封。将反应混合物在40℃下搅拌20小时。完成后,将反应混合物冷却至室温,并用EtOAc稀释。然后将反应混合物通过硅胶塞过滤,并转移至具有磁力搅拌棒的反应瓶(10mL)中。在真空下蒸发溶剂。将无水MeOH(0.5mL)加入到混合物中。在室温下滴加SOCl2(0.30mmol,22μL)。用盖将小瓶密封。将反应混合物在室温下搅拌1小时。完成后,将反应混合物冷却至室温,并在真空下除去溶剂。所得混合物通过制备型薄层色谱法纯化。
紫外线灭活酮的C(sp3)-H碘化的一般程序:在空气下将底物1(0.10mmol)、Pd(TFA)2(0.01mmol,3.3mg)、I2(0.10mmol,25.4mg)和PhI(OAc)2(0.10mmol,32.2mg)称入具有磁力搅拌棒的反应瓶(10mL)中。加入1,4-二噁烷(1.25mL),并将小瓶用盖密封。将反应混合物在40℃下搅拌20小时。完成后,将反应混合物冷却至室温,并用EtOAc稀释。然后将反应混合物通过硅胶塞过滤,并转移至具有磁力搅拌棒的反应瓶(10mL)中。在真空下蒸发溶剂。将无水DCM(0.5mL)和DMF(约10μL)添加到混合物中。在室温下滴加(COCl)2(0.15mmol,13μL)。用盖将小瓶密封。将反应混合物在室温搅拌30分钟,然后蒸发过量的(COCl)2和溶剂。向混合物中加入无水DCM(0.5mL),然后在室温下向混合物中逐滴加入3,5-二甲基苯胺(0.2mmol,25μL)。用盖将小瓶密封。将反应混合物在室温搅拌30分钟。完成后,将反应混合物用EtOAc稀释。然后将反应混合物通过硅藻土塞过滤,并在真空下除去溶剂。所得混合物通过制备型薄层色谱法纯化。
(E)-N-(3,5-二甲基苯基)-2-(((4-碘-3,3-二甲基丁-2-亚基)氨基)氧基)乙酰胺(2a-mono)
按照一般的碘化程序对底物1a进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,获得2a-mono,其为无色油状物(14.1mg,35%)。1H NMR(600MHz,CDCl3)δ7.86(br s,1H),7.19(s,2H),6.76(s,1H),4.62(s,2H),3.31(s,2H),2.29(s,6H),1.96(s,3H),1.29(s,6H)。13C NMR(150MHz,CDCl3)δ168.32,163.16,138.66,136.98,126.25,117.88,73.01,41.14,25.46,21.34,18.61,10.85。HRMS(ESI-TOF)计算值C16H24IN2O2 +[M+H]+:403.0877,实测值:403.0873。
(E)-N-(3,5-二甲基苯基)-2-(((4-碘-3-(碘甲基)-3-甲基丁-2-亚基)氨基)氧基)乙酰胺(2a-di)
按照一般的碘化程序对底物1a进行碘化。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,获得2a-di,其为无色油状物(26.4mg,50%)。1H NMR(600MHz,CDCl3)δ7.75(br s,1H),7.19(s,2H),6.76(s,1H),4.65(s,2H),3.46(ABq,J=10.2Hz,4H),2.29(s,6H),2.02(s,3H),1.41(s,3H)。13C NMR(150MHz,CDCl3)δ167.87,160.45,138.67,136.81,126.34,117.88,73.21,43.67,23.74,21.33,15.46,11.62。HRMS(ESI-TOF)计算值C16H23I2N2O2 +[M+H]+:528.9843,实测值:528.9849。
(E)-N-(3,5-二甲基苯基)-2-(((3-(碘甲基)-3-甲基戊-2-亚基)氨基)氧基]乙酰胺(2b-mono)
按照一般的碘化程序对底物1b进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到2b-mono,其为无色油状物(12.5mg,30%)。1H NMR(600MHz,CDCl3)δ7.83(br s,1H),7.18(s,2H),6.76(s,1H),4.63(ABq,J=16.2Hz,2H),3.31(ABq,J=10.2Hz,2H),2.29(s,6H),1.93(s,3H),1.76-1.70(m,1H),1.56-1.51(m,1H),1.20(s,3H),0.83(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ168.33,162.34,138.68,136.98,126.24,117.81,73.05,44.45,30.46,25.54,22.63,21.34,17.88,11.02,9.38。HRMS(ESI-TOF)计算值C17H26IN2O2 +[M+H]+:417.1033,实测值:417.1029。
(E)-N-(3,5-二甲基苯基)-2-(((4-碘-3-(碘甲基)-3-甲基丁-2-亚基)氨基)氧基)乙酰胺(2b-di)
按照一般的碘化程序对底物1b进行碘化。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到2b-di,其为无色油状物(29.0mg,55%)。1H NMR(600MHz,CDCl3)δ7.72(br s,1H),7.18(s,2H),6.76(s,1H),4.65(s,2H),3.48(ABq,J=10.8Hz,4H),2.29(s,6H),2.01(s,3H),1.73(q,J=7.2Hz,2H),0.82(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ167.81,159.63,138.69,136.78,126.34,117.80,73.23,46.91,27.87,21.33,15.41,11.84,9.62。HRMS(ESI-TOF)计算值C17H25I2N2O2 +[M+H]+:543.0000,实测值:543.0007。
(E)-N-(3,5-二甲基苯基)-2-(((1-(1-(碘甲基)环己基)亚乙基)氨基)氧基]乙酰胺(2c)
按照一般的碘化程序对底物1c进行碘化,不同的是反应时间为3小时。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,获得2c,其为无色油状物(26.5mg,60%)。1H NMR(600MHz,CDCl3)δ7.89(br s,1H),7.20(s,2H),6.75(s,1H),4.64(s,2H),3.29(s,2H),2.29(s,6H),2.02-1.99(m,2H),1.91(s,3H),1.53-1.31(m,8H)。13C NMR(150MHz,CDCl3)δ168.46,161.85,138.60,136.97,126.21,117.93,73.04,44.14,33.77,25.84,22.49,21.32,18.20,10.62。HRMS(ESI-TOF)计算值C19H28IN2O2 +[M+H]+:443.1190,实测值:443.1196。
N-(3,5-二甲基苯基)-2-(((E)-((1S,4R)-3-(碘甲基)-1,3-二甲基双环[2.2.1]庚-2-亚基)氨基)氧基)乙酰胺(2d)
按照一般的碘化程序对底物1d进行碘化,不同的是反应时间为3小时,并且反应时间为3小时。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,获得2d,其为无色油状物(19.1mg,42%)。1H NMR(600MHz,CDCl3)δ7.84(br s,1H),7.16(s,2H),6.77(s,1H),4.55(s,2H),3.45(ABq,J=10.2Hz,2H),2.30(s,6H),2.02-1.97(m,1H),1.96-1.93(m,1H),1.92-1.87(m,2H),1.74-1.68(m,1H),1.58-1.56(m,1H),1.49-1.44(m,1H),1.40(s,3H),1.37(s,3H)。13C NMR(150MHz,CDCl3)δ171.68,168.39,138.73,137.07,126.26,117.65,73.36,54.54,47.64,45.62,43.05,32.19,26.10,23.06,22.84,21.39,8.31。HRMS(ESI-TOF)计算值C20H28IN2O2 +[M+H]+:455.1190,实测值:455.1195。
(E)-2-(((3-苄基-4-碘-3-甲基丁-2-亚基)氨基)氧基)乙酸甲酯(2e-mono)
按照一般的碘化程序对底物1e进行碘化。在通过制备型薄层色谱法(己烷:丙酮=20∶1作为洗脱剂)纯化后,得到2e-mono,其为无色油状物(15.6mg,40%)。1H NMR(600MHz,CDCl3)δ7.28-7.27(m,2H),7.24-7.21(m,1H),7.16-7.15(m,2H),4.58(s,2H),3.73(s,3H),3.29(ABq,J=10.2Hz,2H),2.90(ABq,J=13.8Hz,2H),1.93(s,3H),1.20(s,3H)。13C NMR(150MHz,CDCl3)δ170.57,160.68,136.94,130.24,128.06,126.61,70.53,51.79,44.48,43.28,23.68,17.84,11.84。HRMS(ESI-TOF)计算值C15H21INO3 +[M+H]+:390.0561,实测值:390.0555。
(E)-(2-(((3-苄基-4-碘-3-(碘甲基)丁-2-亚基)氨基)氧基)乙酸甲酯(2e-di)
按照一般的碘化程序对底物1e进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,得到2e-di,其为无色油状物(20.6mg,40%)。1H NMR(600MHz,CDCl3)δ7.30-7.21(m,5H),4.54(s,2H),3.70(s,3H),3.43(ABq,J=10.2Hz,4H),2.97(s,2H),2.00(s,3H)。13C NMR(150MHz,CDCl3)δ170.20,157.66,135.89,129.72,128.29,127.13,70.74,51.85,47.19,40.04,15.86,12.64。HRMS(ESI-TOF)计算值C15H20I2NO3 +[M+H]+:515.9527,实测值:515.9532。
(E)-2-(((3-苄基-3-(碘甲基)戊-2-亚基)氨基)氧基)乙酸甲酯(2f)
按照一般的碘化程序对底物1f进行碘化,不同的是反应时间为3小时。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,获得2f,其为无色油状物(29.0mg,72%)。1H NMR(600MHz,CDCl3)δ7.28-7.25(m,2H),7.23-7.20(m,3H),4.54(ABq,J=16.2Hz,2H),3.70(s,3H),3.24(ABq,J=11.4Hz,2H),2.87(ABq,J=14.4Hz,2H),1.99(s,3H),1.68-1.61(m,2H),0.82(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ170.52,159.60,136.90,129.96,128.10,126.57,70.45,51.74,47.73,40.23,28.90,16.00,12.31,8.33。HRMS(ESI-TOF)计算值C16H23INO3 +[M+H]+:404.0717,实测值:404.0721。
(E)-2-(((3-乙基-3-(碘甲基)-5-苯基戊-2-亚基)氨基)氧基)乙酸甲酯(2g)
按照一般的碘化程序将底物1g碘化,不同的是反应时间为3小时。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到2g,其为无色油状物(30.9mg,74%)。1HNMR(600MHz,CDCl3)δ7.29-7.27(m,2H),7.20-7.17(m,3H),4.64(s,2H),3.73(s,3H),3.50(ABqd,J1=1.2Hz,J2=10.8Hz,2H),2.47(td,J1=4.8Hz,J2=13.2Hz,1H),2.28(td,J1=4.8Hz,J2=13.2Hz,1H),1.94(s,3H),1.93-1.88(m,1H),1.76-1.70(m,1H),1.69-1.64(m,1H),1.58-1.52(m,1H),0.74(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ170.54,159.74,141.87,128.42,128.33,125.90,70.40,51.76,46.42,38.82,30.16,28.97,15.11,11.53,7.75。HRMS(ESI-TOF)计算值C17H25INO3 +[M+H]+:418.0874,实测值:418.0880。
(E)-2-(((6-(4-碘-2,5-二甲基苯氧基)-3-(碘甲基)-3-甲基己-2-亚基)氨基)氧基)乙酸甲酯(2h-mono)
按照一般的碘化程序对底物1h进行碘化。通过制备型薄层色谱法纯化(甲苯∶EtOAc=100∶1作为洗脱剂)后,获得2h-mono,其为无色油状物(29.4mg,50%)。1H NMR(600MHz,CDCl3)δ7.51(s,1H),6.67(s,1H),4.62(s,2H),3.90-3.87(m,2H),3.74(s,3H),3.37(ABq,J=10.8Hz,2H),2.37(s,3H),2.13(s,3H),1.91(s,3H),1.84-1.80(m,1H),1.68-1.63(m,3H),1.22(s,3H)。13C NMR(150MHz,CDCl3)δ170.58,160.35,157.27,139.97,139.43,126.41,112.58,89.04,70.44,67.63,51.76,43.22,34.37,27.96,24.59,23.97,18.20,15.32,11.12。HRMS(ESI-TOF)计算值C19H28I2NO4 +[M+H]+:588.0102,实测值:588.0106。
(E)-2-(((6-(4-碘-2,5-二甲基苯氧基)-3,3-双(碘甲基)己-2-亚基)氨基)氧基)乙酸甲酯(2h-di)
按照一般的碘化程序对底物1h进行碘化。通过制备型薄层色谱法纯化(甲苯∶EtOAc=100∶1作为洗脱剂)后,获得2h-di,其为无色油状物(21.4mg,30%)。1H NMR(600MHz,CDCl3)δ7.51(s,1H),6.67(s,1H),4.64(s,2H),3.89(t,J=6.0Hz,2H),3.74(s,3H),3.51(ABq,J=10.8Hz,4H),2.36(s,3H),2.13(s,3H),1.97(s,3H),1.86-1.83(m,2H),1.66-1.62(m,2H)。13C NMR(150MHz,CDCl3)δ170.30,157.88,157.12,140.02,139.48,126.34,112.48,89.17,70.62,67.13,51.84,46.02,31.95,27.96,25.19,15.96,15.38,11.62。HRMS(ESI-TOF)计算值C19H27I3NO4 +[M+H]+:713.9069,实测值:713.9062。
(E)-2-(((3-碘-2-(碘甲基)-2-甲基-1-苯基亚丙基)氨基)氧基)乙酸甲酯(2i-mono)
按照一般的碘化程序对底物1i进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,得到2i-mono,其为无色油状物(11.3mg,30%)。1H NMR(600MHz,CDCl3)δ7.43-7.40(m,2H),7.38-7.35(m,1H),7.25-7.23(m,2H),4.55(s,2H),3.75(s,3H),3.36(s,2H),1.28(s,6H)。13C NMR(150MHz,CDCl3)δ170.52,162.74,132.95,128.25,128.08,127.40,70.63,51.74,40.74,26.72,19.84。HRMS(ESI-TOF)计算值C14H19INO3 +[M+H]+:376.0404,实测值:376.0400。
(E)-2-(((3-碘-2-(碘甲基)-2-甲基-1-苯基亚丙基)氨基)氧基)乙酸甲酯(2i-di)
按照一般的碘化程序对底物1i进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,获得2i-di,其为无色油状物(21.5mg,43%)。1H NMR(600MHz,CDCl3)δ7.45-7.42(m,2H),7.40-7.38(m,1H),7.34-7.32(m,2H),4.57(s,2H),3.76(s,3H),3.49(ABq,J=10.8Hz,4H),1.41(s,3H)。13C NMR(150MHz,CDCl3)δ170.22,159.30,132.08,128.79,128.31,127.38,70.83,51.87,43.11,24.88,17.66。HRMS(ESI-TOF)计算值C14H18I2NO3 +[M+H]+:501.9371,实测值:501.9375。
(E)-2-(((3-碘-1-(4-甲氧基苯基)-2,2-二甲基亚丙基)氨基)氧基)乙酸甲酯(2j-mono)
按照一般的碘化程序对底物1j进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,获得2j-mono,其为无色油状物(11.7mg,29%)。1H NMR(600MHz,CDCl3)δ7.20-7.17(m,2H),6.95-6.93(m,2H),4.56(s,2H),3.82(s,3H),3.75(s,3H),3.33(s,2H),1.28(s,6H)。13C NMR(150MHz,CDCl3)δ170.57,162.62,159.33,128.76,124.97,113.58,70.61,55.15,51.73,40.92,26.70,20.02。HRMS(ESI-TOF)计算值C15H21INO4 +[M+H]+:406.0510,实测值:406.0515。
(E)-2-(((3-碘-2-(碘甲基)-1-(4-甲氧基苯基)-2-甲基亚丙基)氨基)氧基)乙酸甲酯(2j-di)
按照一般的碘化程序对底物1j进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,获得2j-di,其为无色油状物(22.3mg,42%)。1H NMR(600MHz,CDCl3)δ7.28-7.26(m,2H),6.97-6.94(m,2H),4.57(s,2H),3.82(s,3H),3.76(s,3H),3.48(ABq,J=10.8Hz,4H),1.41(s,3H)。13C NMR(150MHz,CDCl3)δ170.27,159.72,159.26,128.79,124.04,113.76,70.80,55.18,51.85,43.30,24.84,17.79。HRMS(ESI-TOF)计算值C15H20I2NO4 +[M+H]+:531.9476,实测值:531.9471。
(E)-2-(((4-碘-3,3-二甲基-1-苯基丁-2-亚基)氨基)氧基)乙酸甲酯(2k-mono)
按照一般的碘化程序对底物1k进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=10∶1作为洗脱剂)后,得到2k-mono,其为无色油状物(9.7mg,25%)。1H NMR(600MHz,CDCl3)δ7.30-7.27(m,4H),7.22-7.18(m,1H),4.66(s,2H),3.82(s,2H),3.78(s,3H),3.34(s,2H),1.18(s,6H)。13C NMR(150MHz,CDCl3)δ170.56,161.85,136.30,128.52,128.47,126.23,70.58,51.81,40.89,31.78,26.69,20.17。HRMS(ESI-TOF)计算值C15H21INO3 +[M+H]+:390.0561,实测值:390.0569。
(E)-2-(((4-碘-3-(碘甲基)-3-甲基-1-苯基丁-2-亚基)氨基)氧基)乙酸甲酯(2k-di)
按照一般的碘化程序对底物1k进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=10∶1作为洗脱剂)后,得到2k-di,其为无色油状物(25.8mg,50%)。1H NMR(600MHz,CDCl3)δ7.30-7.29(m,4H),7.24-7.20(m,1H),4.70(s,2H),3.85(s,2H),3.79(s,3H),3.45(ABq,J=10.2Hz,4H),1.28(s,3H)。13C NMR(150MHz,CDCl3)δ170.24,158.72,135.61,128.64,126.56,70.82,51.92,43.41,32.11,24.85,17.74。HRMS(ESI-TOF)计算值C15H20I2NO3 +[M+H]+:515.9527,实测值:515.9520。
(E)-2-(((1-氰基-4-碘-3,3-二甲基丁-2-亚基)氨基)氧基)-N-(3,5-二甲基苯基)乙酰胺(2l)
按照一般的碘化程序对底物1l进行碘化不同的是反应温度为80℃。通过制备型薄层色谱法纯化(己烷∶EtOAc=2∶1作为洗脱剂)后,获得2l,其为无色油状物(21.4mg,50%)。1HNMR(600MHz,CDCl3)δ8.06(br s,1H),7.28(s,2H),6.76(s,1H),4.81(s,2H),3.35(s,2H),3.29(s,2H),2.29(s,6H),1.36(s,6H)。13C NMR(150MHz,CDCl3)δ166.71,154.24,138.61,137.06,126.33,117.78,115.38,74.28,41.36,25.44,21.36,15.99,14.26。HRMS(ESI-TOF)计算值C17H23IN3O2 +[M+H]+:428.0829,实测值:428.0822。
(E)-3-((2-((3,5-二甲基苯基)氨基)-2-氧乙氧基)亚氨基)-5-碘-4,4-二甲基戊酸乙酯(2m-mono)
按照一般的碘化程序对底物1m进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到碘化产物,其为3.4∶1(单:双)不可分离的混合物(2m-mono,26.1mg,55%)。1H NMR(600MHz,CDCl3)δ8.63(br s,1H),7.40(s,2H),6.75(s,1H),4.68(s,2H),4.24(q,J=7.2Hz,2H),3.42(s,2H),3.31(s,2H),2.30(s,6H),1.30(t,J=7.2Hz,3H),1.28(s,6H)。13C NMR(150MHz,CDCl3)δ169.29,168.21,157.74,138.34,137.86,125.83,117.73,73.51,61.83,40.63,31.77,25.58,21.43,17.59,14.04。HRMS(ESI-TOF)计算值C19H28IN2O4 +[M+H]+:475.1088,实测值:475.1084。
(E)-3-((2-((3,5-二甲基苯基)氨基)-2-氧乙氧基)亚氨基)-5-碘-4-(碘甲基)-4-甲基戊酸乙酯(2m-di)
按照一般的碘化程序对底物1m进行碘化。在通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到碘化产物,其为3.4∶1(单∶双)不可分离的混合物(2m-di,10.2mg,17%)。1H NMR(600MHz,CDCl3)δ8.60(br s,1H),7.40(s,2H),6.75(s,1H),4.71(s,2H),4.25(q,J=7.2Hz,2H),3.47(s,2H),3.46(ABq,J=10.8Hz,4H),2.30(s,6H),1.42(s,3H),1.31(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ168.80,167.79,154.89,138.36,137.76,125.91,117.72,73.80,62.06,43.30,32.34,29.44,24.00,17.60,15.43。HRMS(ESI-TOF)计算值C19H27I2N2O4 +[M+H]+:601.0055,实测值:601.0051。
(E)-3-((2-((3,5-二甲基苯基)氨基)-2-氧乙氧基)亚氨基)-2-(碘甲基)-2-甲基丁酸乙酯(2n-mono)
按照一般的碘化程序对底物1n进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到碘化产物,其为4.0∶1(单:双)不可分离的混合物(2n-mono,24.8mg,54%)。1H NMR(600MHz,CDCl3)δ7.75(br s,1H),7.18(s,2H),6.77(s,1H),4.66(ABq,J=16.2Hz,2H),4.28-4.17(m,2H),3.59(ABq,J=10.2Hz,2H),2.30(s,6H),1.97(s,3H),1.50(s,3H),1.27(t,J=7.2Hz,3H)。混合物的13C NMR(150MHz,CDCl3)δ170.70,167.78,167.42,167.16,158.93,156.69,138.71,138.70,136.87,136.72,126.43,126.34,117.83,117.76,73.49,73.27,62.96,62.05,56.71,53.06,22.05,21.32,14.12,14.08,12.74,12.64,11.48,10.59。HRMS(ESI-TOF)计算值C18H26IN2O4 +[M+H]+:461.0932,实测值:461.0939。
(E)-3-((2-((3,5-二甲基苯基)氨基)-2-氧乙氧基)亚氨基)-2,2-双(碘甲基)丁酸乙酯(2n-di)
按照一般的碘化程序对底物1n进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到碘化产物,其为4.0∶1(单∶双)不可分离的混合物(2n-di,8.2mg,14%)。1H NMR(600MHz,CDCl3)δ7.68(br s,1H),7.18(s,2H),6.77(s,1H),4.70(s,2H),4.28-4.17(m,2H),3.78(ABq,J=9.6Hz,4H),2.29(s,6H),1.98(s,3H),1.31(t,J=7.2Hz,3H)。混合物的13C NMR(150MHz,CDCl3)δ170.70,167.78,167.42,167.16,158.93,156.69,138.71,138.70,136.87,136.72,126.43,126.34,117.83,117.76,73.49,73.27,62.96,62.05,56.71,53.06,22.05,21.32,14.12,14.08,12.74,12.64,11.48,10.59。HRMS(ESI-TOF)计算值C18H25I2N2O4 +[M+H]+:586.9898,实测值:586.9891。
(E)-2-苄基-2-(碘甲基)-3-((2-甲氧基-2-氧乙氧基)亚氨基)丁酸乙酯(2o)
按照一般的碘化程序对底物1o进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到2o,其为1.6∶1(2o∶原料)不可分离的混合物(32.2mg,60%)。1H NMR(600MHz,CDCl3)δ7.28-7.18(m,4H),7.11-7.09(m,1H),4.57(ABq,J=16.2Hz,2H),4.27-4.18(m,2H),3.73(s,3H),3.41(ABq,J=11.4Hz,2H),3.28(ABq,J=14.4Hz,2H),1.93(s,3H),1.28(t,J=7.2Hz,3H)。混合物的13C NMR(150MHz,CDCl3)δ173.68,170.47,170.17,170.13,156.45,136.99,135.64,130.42,130.04,128.26,128.23,127.94,127.02,126.53,70.74,70.52,61.94,61.06,57.50,53.74,51.82,51.73,41.10,37.69,20.25,14.07,14.03,13.26,13.13,9.90。HRMS(ESI-TOF)计算值C24H30IN2O4 +[M+H]+:537.1245,实测值:537.1240。
(E)-6-(碘甲基)-6,8,8,9,9-五甲基-5-苯基-3,7-二氧杂-4-氮杂-8-硅癸-4-烯-1-酸甲酯(2p-mono)
按照一般的碘化程序对底物1p进行碘化,不同的是反应温度为80℃。通过制备型薄层色谱法纯化(甲苯∶EtOAc=100∶1作为洗脱剂)后,得到2p-mono,其为无色油状物(22.1mg,45%)。1H NMR(600MHz,CDCl3)δ7.40-7.34(m,5H),4.58(s,2H),3.76(s,3H),3.42(ABq,J=9.6Hz,2H),1.68(s,3H),0.80(s,9H),0.14(s,3H),0.01(s,3H)。13C NMR(150MHz,CDCl3)δ170.42,161.17,131.92,128.45,128.22,127.78,76.40,70.82,51.81,27.11,25.89,18.37,17.86,-1.80,-2.48。HRMS(ESI-TOF)计算值C19H31INO4Si+[M+H]+:492.1062,实测值:492.1066。
(E)-6,6-双(碘甲基)-8,8,9,9-四甲基-5-苯基-3,7-二氧杂-4-氮杂-8-硅癸-4-烯-1-酸甲酯(2p-di)
按照一般的碘化程序,对底物1p进行碘化,不同的是反应温度为80℃。通过制备型薄层色谱法纯化(甲苯∶EtOAc=100∶1作为洗脱剂)后,获得2p-di,其为无色油状物(12.3mg,20%)。1H NMR(600MHz,CDCl3)δ7.46-7.44(m,2H),7.42-7.38(m,3H),4.63(s,2H),3.78(s,3H),3.69(ABq,J=10.2Hz,4H),0.92(s,9H),0.15(s,6H)。13C NMR(150MHz,CDCl3)δ170.05,156.26,130.90,129.13,128.42,128.02,76.21,71.10,51.98,26.02,18.68,15.86,-2.14。HRMS(ESI-TOF)计算值C19H30I2NO4Si+[M+H]+:618.0028,实测值:618.0020。
2-(((E)-((E)-5-碘-4,4-二甲基-1-苯基戊-1-烯-3-亚基)氨基)氧基)乙酸甲酯(2q-mono)
按照一般的碘化程序对底物1q进行碘化。通过制备型薄层色谱法纯化(己烷:丙酮=20∶1作为洗脱剂)后,得到2q-mono,其为无色油状物(14.0mg,35%)。1H NMR(600MHz,CDCl3)δ7.49-7.46(m,2H),7.42(d,J=16.8Hz,1H),7.37-7.34(m,2H),7.32-7.29(m,1H),6.56(d,J=16.8Hz,1H),4.68(s,2H),3.78(s,3H),3.41(s,2H),1.36(s,6H)。13C NMR(150MHz,CDCl3)δ170.43,158.24,139.42,136.52,128.80,128.69,126.99,116.05,71.00,51.86,40.72,26.84,20.24。HRMS(ESI-TOF)计算值C16H21INO3 +[M+H]+:402.0561,实测值:402.0555。
2-(((E)-((E)-5-碘-4-(碘甲基)-4-甲基-1-苯基戊-1-烯-3-亚基)氨基)氧基)乙酸甲酯(2q-di)
按照一般的碘化程序对底物1q进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=20∶1作为洗脱剂)后,得到2q-di,其为无色油状物(18.4mg,35%)。1H NMR(600MHz,CDCl3)δ7.49-7.47(m,2H),7.42(d,J=16.8Hz,1H),7.38-7.36(m,2H),7.33-7.31(m,1H),6.49(d,J=16.8Hz,1H),4.69(s,2H),3.79(s,3H),3.55(ABq,J=10.2Hz,4H),1.52(s,3H)。13CNMR(150MHz,CDCl3)δ170.16,155.74,140.17,136.13,129.06,128.74,127.08,115.43,71.17,51.96,43.13,24.92,17.60。HRMS(ESI-TOF)计算值C16H20I2NO3 +[M+H]+:527.9527,实测值:527.9521。
(E)-2-(((5-碘-4,4-二甲基-1-苯基戊-1-炔-3-亚基)氨基)氧基)乙酸甲酯(2r-mono)
按照一般的碘化程序对底物1r进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=10∶1作为洗脱剂)后,得到碘化产物,其为1.9∶1(单:双)不可分离的混合物(2r-mono,20.7mg,52%)。1H NMR(600MHz,CDCl3)δ7.55-7.53(m,2H),7.38-7.34(m,3H),4.73(s,2H),3.78(s,3H),3.45(s,2H),1.39(s,6H)。13C NMR(150MHz,CDCl3)δ169.70,146.92,132.15,129.59,128.40,121.55,101.62,78.23,71.19,51.92,40.46,26.18,16.11。HRMS(ESI-TOF)计算值C16H19INO3 +[M+H]+:400.0404,实测值:400.0400。
(E)-2-(((3-碘-2-(碘甲基)-2-甲基-1-苯基亚丙基)氨基)氧基)乙酸甲酯(2r-di)
按照一般的碘化程序对底物1r进行碘化。通过制备型薄层色谱法纯化(己烷∶EtOAc=10∶1作为洗脱剂)后,得到碘化产物,其为1.9∶1(单∶双)不可分离的混合物(2r-di,8.4mg,16%)。1H NMR(600MHz,CDCl3)δ7.56-7.54(m,2H),7.43-7.39(m,3H),4.75(s,2H),3.79(s,3H),3.59(ABq,J=10.2Hz,4H),1.54(s,3H)。13C NMR(150MHz,CDCl3)δ169.96,143.74,132.21,129.87,128.47,121.15,102.03,77.69,71.39,52.02,42.89,24.71,18.97。HRMS(ESI-TOF)计算值C16H18I2NO3 +[M+H]+:525.9371,实测值:525.9377。
钯环的合成与表征
钯环合成的一般步骤:在空气中,将底物1a(0.1mmol,17.3mg)和Pd(OAc)2(0.12mmol,27.0mg)称重到具有磁力搅拌棒的反应瓶(10mL)中。加入HFIP(1.0mL),并将小瓶用盖密封。将反应混合物在80℃下搅拌12小时。完成后,将反应混合物冷却至室温,并加入PPh3(0.12mmol,31.4mg)。将反应在80℃下再搅拌1小时。完成后,将反应混合物冷却至室温,并用EtOAc稀释。然后将反应混合物通过硅藻土塞过滤。在真空下除去溶剂,并将所得混合物通过制备型薄层色谱法纯化,其中用EtOAc∶MeOH=10∶1作为洗脱剂。
钯环(3)
按照一般的程序对底物1a进行钯化。通过制备型薄层色谱法纯化(EtOAc∶MeOH=10∶1作为洗脱剂)后,得到3,其为白色固体(43.7mg,81%)。1H NMR(600MHz,CDCl3)δ7.60-7.56(m,6H),7.46-7.39(m,9H),4.57(s,2H),1.95(s,3H),1.57(d,J=3.6Hz,2H),1.11(s,6H)。13C NMR(150MHz,CDCl3)δ178.99,172.54,134.04(d,J=12.0Hz),130.60,128.57,128.49,76.00,50.26,40.35,28.65,12.24。HRMS(ESI-TOF)计算值C26H28NO3PPd[M+H]+:539.0842,实测值:539.0850。
除去助剂
除去助剂:在空气下将2g(0.05mmol,20.9mg)称重到具有磁力搅拌棒的反应瓶(10mL)中。加入0.5mL浓HCl(4M)的二噁烷溶液,并用盖密封小瓶。将反应混合物在100℃下搅拌2小时。完成后,将反应混合物冷却至室温,并在真空下除去溶剂。使用甲苯/EtOAc(100∶1)作为洗脱剂,通过制备型薄层色谱法将所得混合物纯化,得到11.6mg 2g-酮(70%收率)。
3-乙基-3-(碘甲基)-5-苯基戊-2-酮(2g-酮)
无色油状物(11.6mg,70%)。1H NMR(600MHz,CDCl3)δ7.30-7.28(m,2H),7.22-7.17(m,3H),3.50(q,J=10.8Hz,2H),2.51-2.46(m,1H),2.30-2.26(m,1H),2.23(s,3H),2.04-1.98(m,1H),1.96-1.90(m,1H),1.82-1.73(m,2H),0.80(t,J=7.2Hz,3H)。13C NMR(150MHz,CDCl3)δ209.25,141.20,128.55,128.26,126.19,54.41,38.04,30.41,28.63,26.02,12.15,8.24。HRMS(ESI-TOF)计算值C14H20IO+[M+H]+:331.0553,实测值:331.0560。
酮的C(sp3)-H芳基化的一般程序:在空气中,将底物1(0.10mmol,18.7mg)、ArI(对碘苯甲酸甲酯为0.20mmol,52.4mg)、Pd(OAc)2(0.01mmol,2.3mg)、AgTFA(0.20mmol,44.2mg)称重到具有磁力搅拌棒的反应瓶(10mL)。加入HFIP(1.0mL),并将小瓶用盖密封。将反应混合物在120℃下搅拌20小时。完成后,将反应混合物冷却至室温,并用EtOAc稀释。然后,将反应混合物通过硅胶塞过滤,并转移至具有磁力搅拌棒的反应瓶(10mL)中。在真空下蒸发溶剂。将无水MeOH(1.0mL)加入到混合物中。在室温下滴加SOCl2(0.30mmol,22μL)。用盖将小瓶密封。将反应混合物在室温搅拌1小时。完成后,将反应混合物冷却至室温,并在真空下除去溶剂。所得混合物通过制备型薄层色谱法纯化。
4-(4-(((1-甲氧基-2-甲基-1-氧基丙-2-基)氧基)亚氨基)戊-2-基)苯甲酸甲酯(2)
按照一般的芳基化程序,使用对碘苯甲酸甲酯作为ArI对底物1进行芳基化。通过制备型薄层色谱法纯化(己烷∶EtOAc=5∶1作为洗脱剂)后,得到2,其E/Z(3.7∶1)混合物(25.1mg,75%)。E异构体(主要)的1H NMR(600MHz,CDCl3)δ7.96-7.94(m,2H),7.27-7.25(m,2H),3.90(s,3H),3.67(s,3H),3.10(六重峰,J=7.2Hz,1H),2.44(ABqd,J1=7.2Hz,J2=14.4Hz,2H),1.79(s,3H),1.42(s,3H),1.39(s,3H),1.24(d,J=6.6Hz,3H)。Z异构体(次要)的1H NMR(600MHz,CDCl3)δ7.98-7.96(m,2H),7.32-7.30(m,2H),3.90(s,3H),3.72(s,3H),3.27(六重峰,J=7.2Hz,1H),2.60(ABqd,J1=7.2Hz,J2=13.2Hz,2H),1.62(s,3H),1.49(s,3H),1.44(s,3H),1.30(d,J=7.2Hz,3H)。E/Z混合物的13C NMR(150MHz,CDCl3)δ174.95,174.92,167.06,156.49,155.99,151.95,151.76,129.74,129.73,128.07,126.99,126.96,80.68,51.95,43.80,37.91,37.01,36.79,24.30,24.17,24.06,24.03,21.76,21.52,20.84,14.50.HRMS(ESI-TOF)计算值C18H26NO5 -[M-H]-:336.1805,实测值:336.1800。
实施例中引用的文件
(a)Peter,M.;Gleiter,R.;Rominger,F.;Oeser,T.Eur.J.Org.Chem.2004,3212.(b)Maruyama,K.;Noguchi-Yachide,T.;Sugita,K.;Hashimoto,Y.;Ishikawa,M.Bioorg.Med.Chem.Lett.2010,20,6661.
Yang,Q.-L.;Li,Y.-Q.;Ma,C.;Fang,P.;Zhang,X.-J.;Mei,T.-S.J.Am.Chem.Soc.2017,139,3293.
Ushijima,S.;Dohi,S.;Moriyama,K.;Togo,H.Tetrahedron,2012,68,1436.
Ohkuma,T.;Sandoval,C.A.;Srinivasan,R.;Lin,Q.;Wei,Y.;Muniz,K.;Noyori,R.J.Am.Chem.Soc.2005,127,8288.
Li,X.;Li,L.;Tang,Y.;Zhong,L.;Cun,L.;Zhu,J.;Liao,J.;Deng,J.J.Org.Chem.2010,75,2981.
Yin,W.;He,H.;Zhang,Y.;Luo,D.;He,H.Synthesis 2014,46,2617.
本文所引用的所有专利和出版物都以与每个单独的出版物均被明确地和单独地指示通过引用整体并入相同的程度通过引用并入本文。
已经采用的术语和表达用作描述性而不是限制性的术语,并且不打算在使用这些术语和表达时排除所示出和描述的特征或其部分的任何等同方案,而是应当认识到,在所要求保护的本发明的范围内可以进行各种修改。因此,应当理解,尽管已经通过优选实施方案和可选特征具体公开了本发明,但是本领域技术人员可以对本文公开的构思进行修改和变型,并且可以将这样的修改和变型视为在由所附权利要求书限定的本发明的范围内。
Claims (10)
1.一种具有β-氢取代基的酮的β-C(sp3)-H碘化的方法,其包括:
使所述酮和氨基氧乙酸在吡啶溶剂中接触以提供相应的肟;
然后,
在非质子溶剂中,在钯(II)盐和乙酸苯碘铵的存在下使所述肟与碘接触;
然后,
在酸性条件下水解所述肟基团,以提供所述产物β-C(sp3)-碘酮。
2.根据权利要求1所述的方法,其中所述氨基氧乙酸是氨基氧乙酸或2,2-二甲基氨基氧乙酸。
3.根据权利要求1所述的方法,其中,所述钯(II)盐是乙酸钯(II)或三氟乙酸钯(II)。
4.根据权利要求1所述的方法,其中所述非质子溶剂是二噁烷或1,1,1,3,3,3-六氟异丙醇。
5.根据权利要求1所述的方法,其中所述肟基团在浓盐酸的二噁烷溶液中水解。
6.一种具有β-氢取代基的酮的β-C(sp3)-H芳基化方法,其包括:
使所述酮和氨基氧乙酸在吡啶溶剂中接触以提供所述相应的肟;
然后,
在非质子溶剂中在钯(II)盐存在下使所述肟与芳基碘化物和三氟乙酸银接触;然后,
在酸性条件下水解所述肟基团,以提供所述产物β-C(sp3)-芳基酮。
7.根据权利要求6所述的方法,其中所述氨基氧乙酸是氨基氧乙酸或2,2-二甲基氨基氧乙酸。
8.根据权利要求6所述的方法,其中,所述钯(II)盐是乙酸钯(II)或三氟乙酸钯(II)。
9.根据权利要求6所述的方法,其中所述非质子溶剂是二噁烷或1,1,1,3,3,3-六氟异丙醇。
10.根据权利要求6所述的方法,其中所述肟基团在浓盐酸的二噁烷溶液中水解。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762546166P | 2017-08-16 | 2017-08-16 | |
US62/546,166 | 2017-08-16 | ||
PCT/US2018/046465 WO2019036349A1 (en) | 2017-08-16 | 2018-08-13 | DIRECTED IODATION OF B-C (SP3) -H AND ARYLATION OF KETONES |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111212824A true CN111212824A (zh) | 2020-05-29 |
CN111212824B CN111212824B (zh) | 2022-08-16 |
Family
ID=65362401
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880066562.2A Active CN111212824B (zh) | 2017-08-16 | 2018-08-13 | 酮的定向β-C(sp3)-H碘化和芳基化 |
Country Status (3)
Country | Link |
---|---|
US (1) | US10875822B2 (zh) |
CN (1) | CN111212824B (zh) |
WO (1) | WO2019036349A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10875822B2 (en) | 2017-08-16 | 2020-12-29 | The Scripps Research Institute | Directed β-C(sp3)#H iodination and arylation of ketones |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113731506B (zh) * | 2021-09-28 | 2023-05-26 | 常州大学 | 杯[4]芳烃酰胺化合物协助钯催化脂肪醛c-h芳基化反应的方法 |
WO2024091805A2 (en) * | 2022-10-27 | 2024-05-02 | The Scripps Research Institute | Heteroarylation of diverse quaternary carbon centers of free carboxylic acids |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4305923A (en) * | 1980-05-08 | 1981-12-15 | Weiler Elmar W | Method for quantitative analysis for limonin |
CN1426388A (zh) * | 2000-04-28 | 2003-06-25 | 日本农药株式会社 | 生产2-卤代苯甲酸的方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111212824B (zh) | 2017-08-16 | 2022-08-16 | 斯克利普斯研究院 | 酮的定向β-C(sp3)-H碘化和芳基化 |
-
2018
- 2018-08-13 CN CN201880066562.2A patent/CN111212824B/zh active Active
- 2018-08-13 WO PCT/US2018/046465 patent/WO2019036349A1/en active Application Filing
- 2018-08-13 US US16/639,401 patent/US10875822B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4305923A (en) * | 1980-05-08 | 1981-12-15 | Weiler Elmar W | Method for quantitative analysis for limonin |
CN1426388A (zh) * | 2000-04-28 | 2003-06-25 | 日本农药株式会社 | 生产2-卤代苯甲酸的方法 |
Non-Patent Citations (5)
Title |
---|
FANG-LIN ZHANG等: "《Functionalization of C(sp3)-H bonds using a transient directing group》", 《SCIENCE (WASHINGTON, DC, UNITED STATES)》 * |
KATHRYN CARR等: "《Substitution at the 4-methyl of lanost-8-en-3-one》", 《JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS》 * |
KE YANG等: "《Catalytic C-H Arylation of Aliphatic Aldehydes Enabled by a Transient Ligand》", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
NURBEY GULIA和OLAFS DAUGULIS: "《Palladium-Catalyzed Pyrazole-Directed sp3 C-H Bond Arylation for the Synthesis of β-Phenethylamines》", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
RU-YI ZHU等: "《Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)-H Bonds》", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10875822B2 (en) | 2017-08-16 | 2020-12-29 | The Scripps Research Institute | Directed β-C(sp3)#H iodination and arylation of ketones |
Also Published As
Publication number | Publication date |
---|---|
WO2019036349A1 (en) | 2019-02-21 |
WO2019036349A8 (en) | 2019-05-09 |
US10875822B2 (en) | 2020-12-29 |
CN111212824B (zh) | 2022-08-16 |
US20200255363A1 (en) | 2020-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111212824B (zh) | 酮的定向β-C(sp3)-H碘化和芳基化 | |
Yanagisawa et al. | Asymmetric protonations of enol derivatives | |
JP5662345B2 (ja) | (r)−及び(s)−3−アミノ−1−ブタノールのエナンチオマー混合物の分離 | |
WO2008155338A2 (en) | Organic compounds | |
JP4787795B2 (ja) | β−アミノ−α−ヒドロキシ−カルボン酸アミドの製造方法 | |
EP2740719B1 (en) | Process for producing a-fluoroaldehydes | |
CN113200933B (zh) | 不对称加成反应合成光学活性苯并羧酸酯类化合物的方法 | |
CN107286202B (zh) | 手性Ugi’s胺和其衍生物及光学异构体的合成方法和应用 | |
ZA200601262B (en) | Cycloakylaminoacid compounds, processes for making and uses thereof | |
JP6148351B2 (ja) | 置換ピロリジン−2−カルボキサミドの不斉合成 | |
CA2793129A1 (en) | Processes and intermediates for preparing a macrocyclic protease inhibitor of hcv | |
CN111187176B (zh) | 一种铜盐催化的制备n-乙烯基酰胺类化合物的方法 | |
Wang et al. | Enantioselective and α‐Regioselective Allylic Amination of Morita‐Baylis‐Hillman Acetates with Simple Aromatic Amines Catalyzed by Planarly Chiral Ligand/Palladium Catalyst | |
WO2006054366A1 (ja) | 軸不斉を有する光学活性な4級アンモニウム塩を用いたアミノ酸およびその誘導体の製造方法 | |
JP5569938B2 (ja) | ピロリジン誘導体及びその製造方法 | |
JP2008115178A (ja) | ジフェニルアラニン−Ni(II)錯体の製造方法 | |
WO2020220651A1 (zh) | 一种手性2-羟基-1,4-二羰基化合物和泛解酸内酯的合成方法 | |
CN107286203B (zh) | 手性Ugi’s胺和其衍生物及光学异构体的制备方法和应用 | |
JP5372556B2 (ja) | α付加型アリル化反応による選択的ホモアリルアルコール誘導体の製造法 | |
JP5344523B2 (ja) | 立体選択的にストレッカー反応を進行させ得る触媒、およびそれを用いたα−アミノニトリル誘導体を立体選択的に製造するための方法 | |
JP4929938B2 (ja) | 光学活性なα−アミノ酸ベンジルエステル類の製造方法 | |
US6924386B2 (en) | Enantioselective reformatsky process for preparing optically active alcohols, amines and derivatives thereof | |
EP1371631A1 (en) | Method for producing optically active salicylaldimine copper complex | |
Boselli et al. | Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters Featuring a Quaternary Stereocenter. Symmetry 2021, 13, 92 | |
US5559268A (en) | Process for the efficient preparation of N-substituted dehydroamino acid esters |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |