CN110305156B - Alkyne derivative containing nitrogen-oxygen bond and preparation method and application thereof - Google Patents
Alkyne derivative containing nitrogen-oxygen bond and preparation method and application thereof Download PDFInfo
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- CN110305156B CN110305156B CN201910666222.XA CN201910666222A CN110305156B CN 110305156 B CN110305156 B CN 110305156B CN 201910666222 A CN201910666222 A CN 201910666222A CN 110305156 B CN110305156 B CN 110305156B
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- China
- Prior art keywords
- nitrogen
- formula
- oxygen bond
- alkyne
- bond
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- 150000001345 alkine derivatives Chemical class 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 10
- 239000010703 silicon Substances 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 46
- 229910052751 metal Inorganic materials 0.000 claims description 24
- 239000002184 metal Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 23
- 229910052741 iridium Inorganic materials 0.000 claims description 17
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 17
- MMAGMBCAIFVRGJ-UHFFFAOYSA-J iridium(3+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene;tetrachloride Chemical group Cl[Ir+]Cl.Cl[Ir+]Cl.CC=1C(C)=C(C)[C-](C)C=1C.CC=1C(C)=C(C)[C-](C)C=1C MMAGMBCAIFVRGJ-UHFFFAOYSA-J 0.000 claims description 15
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 11
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 11
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical group [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 11
- 229940071536 silver acetate Drugs 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 239000011630 iodine Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical class [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- -1 alkyne compound Chemical group 0.000 abstract description 80
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 125000000304 alkynyl group Chemical group 0.000 abstract description 12
- 150000001298 alcohols Chemical class 0.000 abstract description 9
- 230000009467 reduction Effects 0.000 abstract description 9
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 238000005905 alkynylation reaction Methods 0.000 description 15
- 239000002585 base Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000007795 chemical reaction product Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000002390 rotary evaporation Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- JTHLRRZARWSHBE-UHFFFAOYSA-N pent-4-yn-2-ol Chemical compound CC(O)CC#C JTHLRRZARWSHBE-UHFFFAOYSA-N 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- 150000003141 primary amines Chemical class 0.000 description 8
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 238000007306 functionalization reaction Methods 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000010276 construction Methods 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- OBNDGIHQAIXEAO-UHFFFAOYSA-N [O].[Si] Chemical compound [O].[Si] OBNDGIHQAIXEAO-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000012650 click reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 125000004344 phenylpropyl group Chemical group 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FJOACTZFMHZHSC-UHFFFAOYSA-N 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline Chemical compound NC1=C(F)C(F)=C(C(F)(F)F)C(F)=C1F FJOACTZFMHZHSC-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 238000007096 Glaser coupling reaction Methods 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 150000001500 aryl chlorides Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
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- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention belongs to an organic synthesis technologyThe technical field, in particular to an alkyne derivative containing a nitrogen-oxygen bond and a preparation method and application thereof. The invention provides an alkyne derivative containing a nitrogen-oxygen bond, which has a structural formula shown in formula (I), wherein R1And R2Independently selected from hydrogen, alkyl of C1-C20, aryl of C5-C30, substituted aryl of C5-C30 or aromatic heterocyclic radical of C5-C30, R3To replace silicon base. In the invention, the alkyne derivative containing the nitrogen-oxygen bond contains an easily-converted nitrogen-oxygen bond, and primary amine with high added value and polysubstituted alcohol compounds containing alkynyl can be obtained by reduction, so that the alkyne derivative has good application prospect in the field of organic synthesis; in addition, the alkyne derivative containing the nitrogen-oxygen bond contains silicon base which is directly connected with alkyne and can be conveniently detached, and a terminal alkyne compound can be further obtained.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an alkyne derivative containing a nitrogen-oxygen bond, and a preparation method and application thereof.
Background
The alkyne has unique physical properties such as rigidity and optical properties and rich chemical properties such as the molecular complexity of electrophilic addition, nucleophilic addition and Diels-Alder reaction construction, and can quickly and reliably complete the chemical synthesis of color and shape molecules through Click reaction (Click reaction). Even though alkynes are functional groups that are ubiquitous in the fields of materials, medicine, and the like. However, the existing alkyne synthesis method mainly relies on the coupling reaction of terminal alkyne catalyzed by transition metal to construct Csp2-the Csp bond, i.e. the majority still concentrated on alkene, arene-substituted alkyne compounds;
the prior art construction of alkyl-substituted terminal alkynes remains a significant challenge in the field of organic synthesis to date:
1) if the strategy of directly reacting alkyl halide with an alkynylation reagent is used for constructing the internal alkyne with alkyl at both ends, an alkyl metal catalyst species generated in situ by the alkyl halide is easy to generate rapid beta-H elimination reaction to obtain an olefin byproduct, so that target conversion is difficult to obtain;
2) this strategy has good step and atom economy if it is used directly to construct alkyl-substituted terminal alkynes using a strategy of reacting alkyl carbon-hydrogen bonds with alkynylating agents. However, consider the alkyl group Csp3The activity of the-H bond is very low, andalkyl substrates usually contain a plurality of different kinds of alkyl Csp3-H bond, which also enables the exploration of the direct para-alkyl Csp3The direct, site-selective alkynylation of the-H bond remains a great challenge.
Prior art consists of a simple alkyl Csp3-H bond through Csp3Examples of strategies for the selective functionality of the-H bond for the construction of alkynes are very limited and mainly focus on the use of functionalities that are difficult to convert, or/and expensive to synthesize, such as amides of 4-trifluoromethyl-2, 3,5, 6-tetrafluoroaniline, amide derivatives of 8-aminoquinoline as guiding groups to promote Csp3-selective alkynylation of the H bond. Despite its good catalytic efficiency, the difficulty of converting or obtaining the directing group limits its wide application.
In summary, the efficient synthesis of alkyl alkynes, especially alkyne compounds containing functional groups that are easy to be converted, still needs to be further developed, and the types of alkyne derivatives are limited and need to be broadened.
Disclosure of Invention
In view of this, the present invention provides an alkyne derivative containing a nitrogen-oxygen bond, and a preparation method and an application thereof, for providing a new alkyne derivative containing a nitrogen-oxygen bond and widening the kinds of alkyne derivatives containing a nitrogen-oxygen bond.
The specific technical scheme of the invention is as follows:
an alkyne derivative containing a nitrogen-oxygen bond, wherein the structural formula of the alkyne derivative containing the nitrogen-oxygen bond is shown as a formula (I):
wherein R is1And R2Independently selected from hydrogen, alkyl of C1-C20, aryl of C5-C30, substituted aryl of C5-C30 or aromatic heterocyclic radical of C5-C30, R3To replace silicon base.
The alkyne derivative containing the nitrogen-oxygen bond contains the nitrogen-oxygen bond which is easy to convert, can obtain primary amine with high added value and polysubstituted alcohol compounds containing alkynyl through reduction, and has good application prospect in the field of organic synthesis. In addition, the alkyne derivative containing the nitrogen-oxygen bond contains silicon base which is directly connected with the carbon-carbon triple bond of alkyne and can be conveniently detached, and a terminal alkyne compound can be further obtained.
In the invention, the alkyne derivative containing the nitrogen-oxygen bond can be converted into the alkynyl-containing alcohol compound simply, such as reduction by LAH (lithium aluminum hydride) and desilication by TBAF (tetrabutylammonium fluoride), so that the alkynyl-containing alcohol target product can be obtained quantitatively.
Preferably, R1And R2Independently selected from hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, furyl, thienyl, indolyl or pyrrolyl, R3Selected from triisopropyl silicon base, dimethyl tertiary butyl silicon base or oxygen silicon ether containing cyclohexyl.
Further, R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl, phenethyl, phenylpropyl, phenyl, naphthyl, furyl, thienyl, indolyl or pyrrolyl, R3Selected from triisopropylsilyl (-TIPS), dimethyl tert-butylsilyl (-TMS) or cyclohexyl-containing oxysilane.
Further, R1And R2Independently selected from hydrogen, methyl, ethyl, benzyl, 4-fluoro-benzyl, 2-chlorobenzyl, 2-bromobenzyl or phenethyl, R3Is triisopropylsilyl (-TIPS).
Preferably, the nitrogen-oxygen bond-containing alkyne derivative of formula (I) is selected from
The invention also provides a preparation method of the alkyne derivative containing the nitrogen-oxygen bond, which comprises the following steps:
reacting a compound shown in a formula (II) with a compound shown in a formula (III) in the presence of a catalyst to obtain an alkyne derivative containing a nitrogen-oxygen bond shown in the formula (I);
wherein,
R1and R2Independently selected from hydrogen, alkyl of C1-C20, aryl of C5-C30, substituted aryl of C5-C30 or aromatic heterocyclic radical of C5-C30, R3In place of the silicon group, X is hydrogen, bromine, chlorine, iodine or an iodine-containing heterocyclic group, preferably an iodine-containing heterocyclic group
The catalyst is a metal catalyst, and the metal of the metal catalyst is one or more selected from palladium, ruthenium, rhodium and iridium.
The existing alkyne synthesis method mainly relies on the coupling reaction of terminal alkyne catalyzed by transition metal to construct Csp2-a Csp bond, such that the product is concentrated in alkene, arene substituted alkyne compounds. Based on a simple and easily obtained substrate, the rapid construction of the alkyne derivative containing the nitrogen-oxygen bond with important synthetic value through an efficient synthetic strategy still has great challenges. The reason is that: 1) the Sonogashira reaction starting from alkyl halides is often faced with in situ generated Csp3-the metal bond is susceptible to rapid β -H elimination to give an olefinic compound; 2) if directly with an alkyl group Csp3Construction of alkynes starting from H bonds, although having excellent step economics, such reactions are extremely challenging, on the one hand, the relatively flexible alkyl Csp3The high bond energy of H bonds makes activation of such inert chemical bonds very difficult; it is also noted that for a particular nitroxide bond-containing alkyl compound, it often contains a large and complex number and variety of Csp3-H bond, which allows activation of a specific Csp3the-H bond is extremely challenging; more importantly, the alkyl compound containing a nitrogen-oxygen bond is easily oxidized (to a ketone, an aldehyde, a carboxylic acid, or the like) or eliminated (to an olefin isomer) under an oxidizing or basic condition to cause a side reactionSuch that the transition metal catalyzes the direct Csp of the alkyl alcohol3The selective functionalization of the-H bond remains a significant challenge in the field of organic synthesis to date.
To achieve inert alkyl groups Csp3Reactivity and selectivity of the functionalization reactions of H bonds, currently, the targeting strategy is widely applied to selective functionalization reactions of inert C-H bonds. However, the direct alkyl Csp promoted by a common targeting group (e.g., the professor of the Chinji's grant at the institute of Scripps USA uses a polyfluoroanilide-substituted amide compound as a targeting group, and the professor of Chatani's professor of the university of Osaka Japan uses an 8-aminoquinoline-derived amide as a targeting group)3The alkynylation of the-H bond, however, tends to be difficult or expensive to convert, which also makes the overall reaction process more difficult to put into practical use.
Even more challenging is the direct Csp for alkyl compounds containing nitroxide bonds3For the alkynylation of the-H bond, the occurrence of the target conversion is greatly reduced because the alkynylation reagent such as a terminal alkyne or a functionalized alkyne is easy to have a Glaser reaction to obtain a conjugated diyne side reaction under the catalysis of a transition metal.
The compound shown in the formula (II) and the compound shown in the formula (III) are reacted under the action of a catalyst to obtain the alkyne derivative containing the nitrogen-oxygen bond shown in the formula (I), and the Csp of the compound shown in the formula (II) can be efficiently and highly selectively reacted3-H bond is subjected to an alkynylation reaction. In addition, the compound shown in the formula (II) and the compound shown in the formula (III) are widely applied to the fields of medicines, materials and the like, raw materials are common and easy to obtain, the obtained alkyne derivative containing the nitrogen-oxygen bond contains an easily-converted nitrogen-oxygen bond, primary amine with high added value and multi-substituted alcohol compounds containing alkynyl can be obtained through reduction, and the compound has a good application prospect in the field of organic synthesis.
The preparation method is based on metal catalysis, and Csp is directly carried out on the alkyl compound containing the nitrogen-oxygen bond3-H bond alkynylation having the following characteristics: 1) the preparation method of the invention directly uses inert Csp3An alkyne is constructed by starting from an H bond, so that the method has good atom economy and step economy and accords with the synthesis concept of green chemistry;2) the silicon base is used as a substituent of alkyne, can be conveniently removed, and then terminal alkyne is obtained; 3) the product alkyne derivative containing the nitrogen-oxygen bond contains the nitrogen-oxygen bond which is easy to convert, and can further realize the high-efficiency synthesis of primary amine and polysubstituted alkynyl-containing alcohol compounds; 4) the chemical conversion of the preparation method has excellent position specificity, namely, the reaction generates a nitrogen-containing organic metal cyclic intermediate in situ, and then the nitrogen-containing organic metal cyclic intermediate is generated in the first-level Csp3And carrying out regioselective alkynylation reaction on the-H bond to obtain the alkyne derivative containing the nitrogen-oxygen bond.
The preparation method of the invention has the advantages of easy introduction and conversion of the nitrogen-oxygen bond of the alkyl compound based on the nitrogen-oxygen bond, avoids the problems of carbonyl compound or alkene byproduct and the like caused by easy elimination and oxidation side reaction in the catalytic oxidation of carbon-hydrogen bond functionalization reaction, solves the side reaction of oxidation, elimination and the like of the alkyl compound containing the nitrogen-oxygen bond, and provides a simple and efficient strategy for Csp of the alkyne compound containing the nitrogen-oxygen bond3-H bond for efficient transformation. The nitrogen-oxygen bond in the alkyne derivative containing the nitrogen-oxygen bond obtained by the preparation method can be converted into an alkynyl alcohol compound and primary amine through reduction reaction, so that the alkyl compound containing the nitrogen-oxygen bond is converted into the alkynyl alcohol, and the nitrogen-oxygen bond is used as a traceless guide group. The preparation method can realize the conversion of the five-membered metal cyclic intermediate containing nitrogen atoms through the regulation of a nitrogen-oxygen bond structure, thereby achieving the Csp of position selectivity3-an alkynylation of the H bond; and, the conversion is only applied to the first order Csp3-H bond reaction.
The preparation method has wide application range to the substrate, and the obtained position-selective alkyne derivative containing the nitrogen-oxygen bond is easy to convert subsequently and can directly carry out later modification on the alcohol derivative with potential biological activity.
In the present invention, the metal catalyst is more preferably a metal catalyst in which the metal is divalent ruthenium or trivalent rhodium.
Preferably, the reaction of the compound represented by the formula (II) and the compound represented by the formula (III) is specifically as follows:
dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the action of an oxidant and a metal catalyst under the alkaline condition.
Preferably, the metal catalyst is selected from palladium acetate (Pd (OAc)2) Palladium chloride (PdCl)2) Ruthenium trichloride (RuCl)3) Dichloro (p-methylisopropylphenyl) ruthenium (II) dimer ([ Ru (p-cymene) Cl)2]2) Dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer ([ Cp × RhCl)2]2) Pentamethylcyclopentadienyltrisitrilonitrile-bis (hexafluoroantimonic acid) rhodium ([ CpRh (MeCN))3][SbF6]2) And dichloro (pentamethylcyclopentadienyl) iridium (III) dimer ([ Cp IrCl)2]2) More preferably pentamethylcyclopentadienyltrisitrilonitrile-bis (hexafluoroantimonate) rhodium and/or dichloro (pentamethylcyclopentadienyl) iridium (III) dimer.
When the metal catalyst is dichloro (pentamethylcyclopentadienyl) iridium (III) dimer, the reaction is preferably carried out with the addition of bistrifluoromethanesulfonylimide silver salt (AgNTf)2) The bis (trifluoromethanesulfonyl) imide silver salt is used as a chloride ion capture agent and is used together with dichloro (pentamethylcyclopentadienyl) iridium (III) dimer to capture chloride ions on the dichloro (pentamethylcyclopentadienyl) iridium (III) dimer, so that trivalent iridium catalyst species which are more electron-deficient are generated in situ, and the electrophilicity of the trivalent iridium catalyst species is enhanced.
In the present invention, R1And R2Independently selected from hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, furyl, thienyl, indolyl or pyrrolyl, R3Selected from triisopropyl silicon base, dimethyl tertiary butyl silicon base or oxygen silicon ether containing cyclohexyl.
Further, R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl, phenethyl, phenylpropyl, phenyl, naphthyl, furyl, thienyl, indolyl or pyrrolyl, R3Selected from triisopropylsilyl (-TIPS), dimethyl tert-butylsilyl (-TMS) or cyclohexyl-containing oxysilane.
Further, R1And R2Independently selected from hydrogen, methyl, ethyl, benzyl, 4-fluoro-benzyl, 2-chlorobenzyl, 2-bromobenzyl or phenethyl, R3Is triisopropylsilyl (-TIPS).
In the present invention, the nitrogen-oxygen bond-containing alkyne derivative represented by the formula (I) is selected from
The compound shown in the formula (II) is obtained by carrying out Mitsnobu reaction and hydrazine hydrate hydrazinolysis on commercially available alcohol and N-hydroxyphthalimide to obtain corresponding primary amine and then condensing with cyclohexanone.
The compound of formula (II) is preferably
The compound of formula (III) is selected from
Preferably, the oxidant is selected from one or more of silver acetate, silver carbonate, silver triflate, silver nitrate, copper acetate, cuprous halide, cupric halide, ferric trihalide and ferric nitrate, more preferably cupric acetate;
the base for adjusting the basic condition is selected from one or more of sodium acetate, cesium acetate, potassium acetate, sodium carbonate, lithium carbonate and potassium phosphate, and more preferably sodium acetate.
Preferably, the reaction temperature is 60 ℃ to 150 ℃, more preferably 80 ℃ to 120 ℃, and further preferably 100 ℃;
the reaction time is 8 to 48 hours, and more preferably 8 to 36 hours.
In the present invention, the inert solvent is selected from toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol or acetone, and more preferably 1, 2-dichloroethane.
Preferably, the molar ratio of the compound shown in the formula (II) to the compound shown in the formula (III) is 1: 1-1: 4;
the amount of the metal catalyst is 1 mol% to 5 mol%, more preferably 2 mol%, of the amount of the compound represented by the formula (II).
In the invention, the using amount of the alkali is 5-50 mol% of that of the compound shown in the formula (II), and more preferably 15 mol%;
the amount of the oxidizing agent is 10 to 300 mol%, more preferably 30 mol%, of the amount of the compound represented by the formula (II).
The concentration of the compound shown in the formula (II) in the inert solvent is 0.1-3.0 mol/L, preferably 0.2 mol/L; the concentration of the compound represented by the formula (III) in the inert solvent is 0.5mol/L to 3.0mol/L, preferably 1.0 mol/L.
In the present invention, the process for producing an alkyne derivative containing a nitrogen-oxygen bond preferably comprises the steps of: under the air atmosphere, sequentially adding a compound (0.1mmol) shown in a formula (II), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonyl) imide silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) into a reactor, injecting a 1, 2-dichloroethane solution (1.0mL) of the compound (0.3mmol) shown in the formula (III) into the reactor by using a syringe, placing the reactor at 100 ℃ for reaction for 12 hours, determining the reaction end through thin-layer chromatography analysis, performing suction filtration on a reaction solution by using kieselguhr, performing rotary evaporation and concentration on silica gel with 400 meshes to prepare dry powder through column chromatography, separating a reaction product by using the silica gel with 400 meshes for 5g, and using a developing agent in a volume ratio of 200:1 to 20: 1 and ethyl acetate to obtain the alkyne derivative containing the nitrogen-oxygen bond.
Aiming at the problem that the nitrogen oxide compound derived from the alkyl alcohol is easy to generate rearrangement, oxidation and elimination reactions to obtain byproducts such as ketone, carbonyl compound, olefin and the like, the direct oxidation Csp promoted by the alcoholic hydroxyl group3The few reports of the functionalization reaction of the H bond, the preparation method of the invention not only provides a high-efficiency and high-selectivity synthesis method of alkyne derivatives containing nitrogen-oxygen bonds, but also provides alcohol-derived nitrogen oxide-induced oxidation Csp3Functionalization of the-H bondProvides a new idea. In addition, the alkyne derivative containing the nitrogen-oxygen bond contains an easily-converted nitrogen-oxygen bond, primary amine and multi-substituted alcohol compounds containing alkynyl with high additional values can be obtained through reduction, two fine chemicals with high additional values can be rapidly obtained through one chemical conversion, and therefore, the alkyne derivative also can be alkyl Csp with position selectivity3The field of functionalization reactions of the-H bond provides a certain theoretical guidance.
Alkyl compounds directed against common nitrogen-oxygen bond-containing bonds tend to contain a large and abundant amount of Csp3-H bond (primary, secondary, tertiary Csp)3-H bond, etc., even with an aryl group Csp2-H bond), the catalytic system of the invention can effectively identify different kinds of C-H bonds, and five-membered organic metal cyclic intermediate is generated in situ through metal catalyst and substrate nitrogen atom in reaction, and the position specificity is in first-order Csp3The alkynylation reaction is carried out on the-H bond to obtain the corresponding alkyne derivative containing the nitrogen-oxygen bond, and the position-specific Csp can be realized3the-H bond is alkynylated and has important synthetic value.
The invention also provides the application of the alkyne derivative containing the nitrogen-oxygen bond in the technical scheme and/or the alkyne derivative containing the nitrogen-oxygen bond prepared by the preparation method in the technical scheme in the preparation of medicaments.
The alkyne derivative containing the nitrogen-oxygen bond contains the nitrogen-oxygen bond which is easy to convert, can obtain primary amine with high added value and polysubstituted alcohol compounds containing alkynyl through reduction, and has good application prospect in the field of organic synthesis. And, R3When the alkyne derivative containing the nitrogen-oxygen bond is used for replacing silicon base, the alkyne derivative containing the nitrogen-oxygen bond contains the silicon base which is directly connected with the carbon-carbon triple bond of the alkyne and can be conveniently removed, and a terminal alkyne compound can be further obtained.
In the invention, the alkyne derivative containing the nitrogen-oxygen bond can be converted into the alkynyl-containing alcohol compound simply, such as reduction by LAH (lithium aluminum hydride) and desilication by TBAF (tetrabutylammonium fluoride), so that the alkynyl-containing alcohol target product can be obtained quantitatively.
In summary, the invention provides an alkyne derivative containing a nitrogen-oxygen bond, the structural formula of the alkyne derivative containing the nitrogen-oxygen bond is shown as formula (I), wherein R is1And R2Independently selected from hydrogen, alkyl of C1-C20, aryl of C5-C30, substituted aryl of C5-C30 or aromatic heterocyclic radical of C5-C30, R3To replace silicon base. In the invention, the alkyne derivative containing the nitrogen-oxygen bond contains an easily-converted nitrogen-oxygen bond, can obtain primary amine with high added value and a polysubstituted alcohol compound containing alkynyl through reduction, and has good application prospect in the field of organic synthesis. In addition, the alkyne derivative containing the nitrogen-oxygen bond contains silicon base which is directly connected with alkyne and can be conveniently detached, and a terminal alkyne compound can be further obtained.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR of cyclohexanone O- (5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1a) provided in example 1 of the present invention1H, spectrogram;
FIG. 2 shows NMR of Cyclohexanone O- (5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1a) in example 1 of the present invention13C, spectrum;
FIG. 3 shows the NMR of cyclohexanone O- (2-methyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1b) provided in example 2 of the present invention1H, spectrogram;
FIG. 4 shows the NMR of cyclohexanone O- (2-methyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1b) provided in example 2 of the present invention13C, spectrum;
FIG. 5 shows the NMR of cyclohexanone O- (6- (triisopropylsilyl) -5-hexynyl-3-yl) oxime ether (1c) provided in example 3 of the present invention1H, spectrogram;
FIG. 6 shows cyclohexanone O- (6- (triisopropylsilyl) -5-hexynyl-3-yl) oxime as provided in example 3 of the present inventionNuclear magnetic resonance of Ether (1c)13C, spectrum;
FIG. 7 shows the NMR of cyclohexanone O- (1-phenyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1d) provided in example 4 of the present invention1H, spectrogram;
FIG. 8 shows NMR of Cyclohexanone O- (1-phenyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1d) according to example 4 of the present invention13C, spectrum;
FIG. 9 shows NMR spectra of Cyclohexanone O- (1- (4-fluorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1e) provided in example 5 of the present invention1H, spectrogram;
FIG. 10 shows the NMR of cyclohexanone O- (1- (4-fluorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1e) provided in example 5 of the present invention13C, spectrum;
FIG. 11 shows the NMR of Cyclohexanone O- (1- (2-chlorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1f) according to example 6 of the present invention1H, spectrogram;
FIG. 12 shows NMR of Cyclohexanone O- (1- (2-chlorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1f) according to example 6 of the present invention13C, spectrum;
FIG. 13 shows NMR spectra of cyclohexanone O- (1- (2-bromophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1g) provided in example 7 of the present invention1H, spectrogram;
FIG. 14 shows the NMR of cyclohexanone O- (1- (2-bromophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1g) provided in example 7 of the present invention13C, spectrum;
FIG. 15 shows the NMR of cyclohexanone O- (1-phenyl-6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1h) provided in example 8 of the present invention1H, spectrogram;
FIG. 16 shows the NMR of cyclohexanone O- (1-phenyl-6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1h) provided in example 8 of the present invention13C, spectrum;
FIG. 17 shows NMR of 4-pentyn-2-ol (4a) according to example 9 of the present invention1H, spectrogram;
figure 18 is theNuclear magnetic resonance of 4-pentyn-2-ol (4a) provided in inventive example 913And C, spectrum.
Detailed Description
The invention provides an alkyne derivative containing a nitrogen-oxygen bond, a preparation method and application thereof, which are used for providing a novel alkyne derivative containing a nitrogen-oxygen bond and widening the variety of the alkyne derivative containing a nitrogen-oxygen bond.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
For a further understanding of the invention, reference will now be made in detail to the following examples.
Example 1
This example carries out the preparation of cyclohexanone O- (5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1a), having the formula:
under the air atmosphere, a nitroxy bond-containing compound 2a (15.5mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing alkyne compound 3a (54.0mg,0.3mmol) is injected into the reactor by a syringe, the reactor is placed at 120 ℃ for reaction for 24 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, dried powder is prepared by rotary evaporation and concentration by using 400-mesh silica gel, the reaction product is separated by adopting 400-mesh silica gel column chromatography, 5g of a developing agent is prepared by a volume ratio of 200:1 to 20: 1 with ethyl acetate to give cyclohexanone O- (5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1a) in 25.1mg, purity 95% and yield 75%.
The nuclear magnetic resonance detection of cyclohexanone O- (5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1a) is shown in FIGS. 1 to 2, and the results are:1H NMR(400MHz,CDCl3):δ4.27-4.23(m,1H),2.64(dd,J＝4.0Hz,16.8Hz,1H),2.46-2.40(m,3H),2.18(t,J＝6.0Hz,2H),1.66-1.65(m,2H),1.59-1.58(m,4H),1.34(d,J＝6.4Hz,3H),1.07-1.05(m,21H)；13C NMR(100MHz,CDCl3):δ160.3,105.4,81.8,76.4,32.3,27.1,26.8,25.9,25.8,25.4,18.6,18.5,11.3。
this example shows that a compound containing a nitrogen-oxygen bond can realize the beta-position Csp of an oxygen atom with the assistance of a nitrogen-oxygen bond3The alkynylation of the-H bond, the reaction of this example, has excellent site selectivity.
Example 2
This example carries out the preparation of cyclohexanone O- (2-methyl-5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1b), the reaction scheme of which is shown below:
under the air atmosphere, a nitroxy bond-containing compound 2b (16.9mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing alkyne compound 3a (54.0mg,0.3mmol) is injected into the reactor by a syringe, the reactor is placed at 120 ℃ for reaction for 24 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, dried powder is prepared by rotary evaporation and concentration by using 400-mesh silica gel, the reaction product is separated by adopting 400-mesh silica gel column chromatography, 5g of a developing agent is prepared by a volume ratio of 100:1 to 20: 1 with ethyl acetate to give cyclohexanone-O- (2-methyl-5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1b), 27.2mg, 95% purity, 78% yield.
The NMR detection of cyclohexanone-O- (2-methyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1b) is shown in FIGS. 3 to 4, with the results:1H NMR(400MHz,CDCl3):δ＝2.57(s,2H),2.49-2.40(m,2H),2.18(t,J＝6.0Hz,2H),1.70-1.60(m,2H),1.58-1.56(m,4H),1.37(s,6H),1.08-1.07(m,21H)；13C NMR(100MHz,CDCl3):δ＝158.2,105.4,80.4,77.5,31.4,30.7,26.1,25.0,24.8,24.2,17.6,10.3。
this example shows that a compound containing a nitrogen-oxygen bond can realize the beta-position Csp of an oxygen atom with the assistance of a nitrogen-oxygen bond3The alkynylation of the-H bond, the reaction of this example, has excellent site selectivity.
Example 3
This example carries out the preparation of cyclohexanone O- (6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1c) having the reaction formula:
under the air atmosphere, a nitroxy bond-containing compound 2c (16.9mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing an alkyne compound 3b (78mg,0.3mmol) is injected into the reactor by a syringe and placed at 120 ℃ for reaction for 24 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, and is subjected to rotary evaporation and concentration by 400-mesh silica gel to prepare dry powder, and then the reaction product is separated by column chromatography, 5g of 400-mesh silica gel is used, and a developing agent is used in a volume ratio of 100:1 to 20: 1 with ethyl acetate to give cyclohexanone O- (6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1c) in 24.8mg, purity 95% and yield 71%.
The nuclear magnetic resonance detection of cyclohexanone O- (6- (triisopropylsilyl) -5-hexynyl-3-yl) oxime ether (1c) is shown in FIGS. 5 to 6, and the results are:1H NMR(400MHz,CDCl3):δ＝4.08-4.02(m,1H),2.61(dd,J＝4.4Hz,16.8Hz,1H),2.51-2.43(m,3H),2.18(m,2H),1.73-1.64(m,2H),1.59-1.58(m,6H),1.11-1.04(m,21H),0.95(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ＝160.4,105.5,81.7,81.3,32.3,27.1,25.9,25.8,25.43,25.41,24.6,18.6,18.5,17.7,11.3,9.7。
this example shows that a compound containing a nitrogen-oxygen bond can realize the beta-position Csp of an oxygen atom with the assistance of a nitrogen-oxygen bond3Alkynylation of the-H bond even if the primary Csp at the gamma position is present in the compound containing the nitroxide bond3-a H bond.
Example 4
This example carries out the preparation of cyclohexanone O- (1-phenyl-5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1d) having the reaction formula:
under the air atmosphere, a nitroxy bond-containing compound 2d (23.1mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing an alkyne compound 3b (78mg,0.3mmol) is injected into the reactor by a syringe and placed at 120 ℃ for reaction for 18 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, and is subjected to rotary evaporation and concentration by 400-mesh silica gel to prepare dry powder, and then the reaction product is separated by column chromatography, 5g of 400-mesh silica gel is used, and a developing agent is used in a volume ratio of 200:1 to 20: 1 with ethyl acetate to give cyclohexanone O- (1-phenyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1d), 32.9mg, purity 95%, yield 80%.
The nuclear magnetic resonance detection of cyclohexanone O- (1-phenyl-5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1d) is shown in FIGS. 7 to 8, and the results are:1H NMR(400MHz,CDCl3):δ7.27-7.26(m,4H),7.23-7.18(m,1H),4.37-4.31(m,1H),3.11(dd,J＝5.6Hz,8.8Hz,1H),3.02(dd,J＝6.8Hz,14.0Hz,1H),2.58-2.49(m,2H),2.47-2.43(m,2H),2.19-2.16(m,2H),1.65-1.56(m,6H),1.25(s,2H),1.10-1.09(m,19H)；13C NMR(100MHz,CDCl3):δ＝160.6,138.4,129.7,128.1,126.1,105.3,82.5,80.8,38.4,32.2,29.7,27.1,25.8,24.2,18.7,18.6,18.5,18.4,17.7,12.3,11.4,11.2。
this example shows that compounds containing a nitrogen-oxygen bond can achieve regioselective beta-position Csp of an oxygen atom with the aid of a nitrogen-oxygen bond3The ethynylation of the-H bond does not occur at the usual more reactive benzylic or aryl C-H bond positions.
Example 5
This example carries out the preparation of cyclohexanone O- (1- (4-fluorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1e) having the formula:
under the air atmosphere, a nitroxy bond-containing compound 2e (24.9mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing alkyne compound 3a (54.0mg,0.3mmol) is injected into the reactor by a syringe, the reactor is placed at 120 ℃ for reaction for 20 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, dried powder is prepared by rotary evaporation and concentration by using 400-mesh silica gel, the reaction product is separated by adopting 400-mesh silica gel column chromatography, 5g of a developing agent is prepared by a volume ratio of 100:1 to 20: 1 with ethyl acetate to give cyclohexanone O- (1- (4-fluorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1e), 31.3mg, purity 95%, yield 73%.
NMR detection of Cyclohexanone O- (1- (4-fluorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1e) with reference to FIGS. 9 to 10 gave the following results:1H NMR(400MHz,CDCl3):δ7.33-7.31(m,2H),7.16-7.13(m,2H),4.45-4.41(m,2H),3.26(dd,J＝4.8Hz,14.0Hz,1H),3.11(dd,J＝8.0Hz,14.0Hz,1H),2.62(d,J＝5.2Hz,2H),2.49-2.35(m,2H),2.13(d,J＝6.0Hz,2H),1.63-1.54(m,6H),1.09-1.08(m,21H)；13C NMR(100MHz,CDCl3):δ＝159.6,135.5,133.5,130.9,128.3,126.6,125.3,104.0,81.5,78.1,35.5,31.1,26.0,24.8,24.7,24.5,24.0,17.6,17.54,17.48,16.7,11.3,10.3。
this exampleIndicating that the compound containing nitrogen-oxygen bond can realize regioselective beta-position Csp of oxygen atom with the help of nitrogen-oxygen bond3The reaction is compatible with fluorine functional groups which are common in the fields of materials and medicines.
Example 6
This example carries out the preparation of cyclohexanone O- (1- (2-chlorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1f) having the formula:
under the air atmosphere, a nitroxy bond-containing compound 2f (26.5mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) are sequentially added into a reactor, an acetone solution (1.0mL) containing an alkyne compound 3c (85.6mg,0.2mmol) is injected into the reactor by a syringe and placed at 120 ℃ for reaction for 16 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, dried powder is prepared by rotary evaporation and concentration by 400-mesh silica gel, the reaction product is separated by adopting 400-mesh silica gel column chromatography, 5g of 400-mesh silica gel is used as a developing agent, and the volume ratio is 100: 1-20: 1 with ethyl acetate to give cyclohexanone O- (1- (2-chlorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1f), 33.8mg, purity 95%, yield 76%.
NMR detection of Cyclohexanone O- (1- (2-chlorophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1f) was performed with reference to FIGS. 11 to 12, and the results were:1H NMR(400MHz,CDCl3):δ7.21(dd,J＝5.6Hz,8.4Hz,1H),6.95(t,J＝8.8Hz,2H),4.33-4.27(m,1H),3.09(dd,J＝5.6Hz,9.6Hz,1H),2.98(dd,J＝6.8Hz,14.0Hz,1H),2.56(dd,J＝4.0Hz,16.8Hz,1H),2.45(dd,J＝7.2Hz,16.8Hz,3H),2.19-2.16(m,2H),1.60-1.57(m,6H),1.10-1.07(m,21H)；13C NMR(100MHz,CDCl3):δ＝160.8,134.0,133.9,131.1,115.0,114.8,105.1,82.6,80.7,37.5,32.2,29.7,27.1,25.83,25.78,25.6,24.2,18.7,18.5,17.8,17.7,12.3,11.3。
this implementationThe illustration shows that the compound containing nitrogen-oxygen bond can realize the regioselectivity beta-position Csp of oxygen atom with the help of nitrogen-oxygen bond3The alkynylation of the-H bond, without reaction at the benzylic or aryl chloride position, shows good regioselectivity and chemoselectivity.
Example 7
This example carries out the preparation of cyclohexanone O- (1- (2-bromophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1g), having the formula:
under the air atmosphere, 2g (30.9mg,0.1mmol) of a nitrogen-oxygen bond-containing compound, 3.2mg of dichloro (pentamethylcyclopentadienyl) iridium (III) dimer, 5.8mg of bis (trifluoromethanesulfonyl) imide silver salt, 14.8mg of lithium carbonate and 33.4mg of silver acetate are sequentially added into a reactor, an acetone solution (1.0mL) containing alkyne compound 3a (54.0mg,0.3mmol) is injected into the reactor by a syringe, the reactor is placed at 120 ℃ for reaction for 24 hours, the reaction is determined to be finished by thin-layer chromatography analysis, the reaction solution is subjected to suction filtration by diatomite, dried powder is prepared by rotary evaporation and concentration by using 400-mesh silica gel, then the reaction product is separated by adopting 400-mesh silica gel column chromatography, 5g of a developing agent is prepared by a volume ratio of 100: 1-20: 1 with ethyl acetate to give cyclohexanone O- (1- (2-bromophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1g) in 31.8mg, purity 95% and yield 65%.
NMR detection of Cyclohexanone O- (1- (2-bromophenyl) -5- (triisopropylsilyl) -4-pentyn-2-yl) oxime ether (1g) was performed with reference to FIGS. 13 to 14, and the results were:1H NMR(400MHz,CDCl3):δ＝7.52(d,J＝8.4Hz,1H),7.33(d,J＝7.6Hz,1H),7.20(t,J＝7.2Hz,1H),7.07-7.03(m,1H),4.47-4.47(m,1H),3.29-3.09(m,2H),2.65-2.63(m,1H),2.44-2.39(m,2H),2.19-2.13(m,3H),163-1.54(m,6H),1.26-1.25(m,3H),1.13-1.02(m,21H)；13C NMR(100MHz,CDCl3):δ＝159.6,158.8,137.6,137.3,131.6,130.9,130.8,126.6,126.0,124.0,104.0,81.5,78.1,40.7,38.0,31.2,31.1,26.05,26.02,24.9,24.8,24.7,24.5,24.4,17.7,10.3。
this example shows that compounds containing a nitrogen-oxygen bond can achieve regioselective beta-position Csp of an oxygen atom with the aid of a nitrogen-oxygen bond3The reaction has excellent position selectivity. More importantly, the reaction is compatible with aryl bromide compounds that are widely used in coupling reactions.
Example 8
This example carries out the preparation of cyclohexanone O- (1-phenyl-6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1h), having the reaction formula:
under the air atmosphere, sequentially adding a nitrogen-oxygen bond-containing compound for 2h (24.5mg,0.1mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (3.2mg), bis (trifluoromethanesulfonylimide) silver salt (5.8mg), lithium carbonate (14.8mg) and silver acetate (33.4mg) into a reactor, injecting an acetone solution (1.0mL) containing alkyne compound 3a (78mg,0.3mmol) into the reactor by using a syringe, placing the reactor at 120 ℃ for reaction for 24h, determining the end of the reaction through thin-layer chromatography analysis, carrying out suction filtration on the reaction solution by using kieselguhr, carrying out rotary evaporation and concentration on 400-mesh silica gel to obtain dry powder, separating the reaction product by using column chromatography, 5g of 400-mesh silica gel, and developing agent in a volume ratio of 100:1 to 20: 1 with ethyl acetate to give cyclohexanone O- (1-phenyl-6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1h), 33.1mg, 95% purity, 78% yield.
The nuclear magnetic resonance detection of cyclohexanone O- (1-phenyl-6- (triisopropylsilyl) -5-hexyn-3-yl) oxime ether (1h) is shown in figures 15 to 16, and the results are as follows:1H NMR(400MHz,CDCl3):δ＝7.19-7.17(m,2H),7.13-7.07(m,3H),4.13-4.01(m,1H),2.71-2.39(m,3H),2.47-2.39(m,3H),2.13-2.10(m,2H),1.59-1.52(m,6H),1.18-1.17(m,2H),1.04-0.94(m,21H)；13C NMR(100MHz,CDCl3):δ＝160.6,142.3,128.45,128.42,128.3,125.7,105.3,80.0,79.4,37.5,34.3,32.35,32.28,31.8,31.7,25.9,25.45,25.40,18.6,11.3。
the true bookThe examples show that the compound containing nitrogen-oxygen bonds can realize beta-position Csp of oxygen atoms with the assistance of nitrogen-oxygen bonds3The reaction has excellent position selectivity, the reaction does not react at the common more active benzyl position or aryl C-H bond, and the beta position secondary Csp is simultaneously present in the substrate2by-H bonds, the reaction only occurs singly in the primary Csp3-H bond.
Example 9
This example carries out the preparation of 4-pentyn-2-ol (4a) having the formula:
lithium aluminum hydride (LAH, 19mg, 0.5mmol) was added to a reactor containing a solution of cyclohexanone O- (5- (triisopropylsilyl) -4-pentynyl-2-yl) oxime ether (1a) (67.0mg,0.2mmol) in diethyl ether (4.0mL) under a nitrogen atmosphere, and reacted at room temperature for 48 hours. The reaction solution was filtered with suction through celite, tetrabutylammonium fluoride (104.4mg,0.4mmol) was added, and the reaction was continued at room temperature for 1 hour. Filtering the reaction solution by using diatomite, performing rotary evaporation and concentration on 400-mesh silica gel to prepare dry powder, and separating a reaction product by adopting column chromatography, wherein the volume ratio of the 400-mesh silica gel is 5g, and the developing agent is 100: 1-20: 1 to obtain alkynyl-containing alcohol derivative 4-pentyn-2-ol (4a), 14.4mg, 95% purity and 86% yield.
Nmr examination of 4-pentyn-2-ol (4a) with reference to fig. 17-18 resulted in:1H NMR(400MHz,CDCl3):δ＝3.92-3.91(m,1H),2.68-2.48(m,1H),2.36-2.25(m,2H),2.03-2.02(m,1H),1.23-1.21(m,3H)；13C NMR(100MHz,CDCl3):δ＝80.9,66.1,28.7,22.1。
this example shows that the alkyne derivative containing a nitrogen-oxygen bond of the present invention can be subjected to reduction and desilication reactions to obtain an alcohol derivative containing a terminal alkyne, thereby realizing formal alcohol-induced Csp3-an ethynylation of the H bond.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (3)
1. A method for preparing an alkyne derivative containing a nitrogen-oxygen bond is characterized by comprising the following steps:
reacting a compound shown in a formula (II) with a compound shown in a formula (III) in the presence of a catalyst to obtain an alkyne derivative containing a nitrogen-oxygen bond shown in the formula (I);
wherein,
R1and R2Independently selected from hydrogen, alkyl of C1-C20, aryl of C5-C30, substituted aryl of C5-C30 or aromatic heterocyclic radical of C5-C30, R3For replacing silicon base, X is hydrogen, bromine, chlorine, iodine or an iodine-containing heterocyclic group;
the catalyst is a metal catalyst, and the metal of the metal catalyst is selected from iridium;
the metal catalyst is selected from dichloro (pentamethylcyclopentadienyl) iridium (III) dimer;
the reaction of the compound shown in the formula (II) and the compound shown in the formula (III) in the presence of a catalyst is specifically as follows:
dissolving a compound shown as a formula (II) and a compound shown as a formula (III) in an inert solvent, and reacting under the action of an oxidant, bis (trifluoromethanesulfonyl) imide silver salt and a metal catalyst under an alkaline condition;
the oxidant is selected from silver acetate;
the base to adjust the alkaline conditions is selected from lithium carbonate.
2. The method for preparing the compound of claim 1, wherein the reaction temperature is 60 ℃ to 150 ℃;
the reaction time is 8-48 h.
3. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is 1:1 to 1: 4;
the dosage of the metal catalyst is 1-5 mol% of the dosage of the compound shown in the formula (II).
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