CN104529889B - 一种杂环甲基化合物的脱水c-烷基化方法 - Google Patents
一种杂环甲基化合物的脱水c-烷基化方法 Download PDFInfo
- Publication number
- CN104529889B CN104529889B CN201410723220.7A CN201410723220A CN104529889B CN 104529889 B CN104529889 B CN 104529889B CN 201410723220 A CN201410723220 A CN 201410723220A CN 104529889 B CN104529889 B CN 104529889B
- Authority
- CN
- China
- Prior art keywords
- reaction
- dehydration
- cdcl
- heterocyclic
- nmr
- 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.)
- Expired - Fee Related
Links
- -1 heterocyclic methyl compound Chemical class 0.000 title claims abstract description 32
- 230000018044 dehydration Effects 0.000 title claims abstract description 19
- 238000006297 dehydration reaction Methods 0.000 title claims abstract description 19
- 230000029936 alkylation Effects 0.000 title claims abstract description 13
- 238000005804 alkylation reaction Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 119
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002152 alkylating effect Effects 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 150000002391 heterocyclic compounds Chemical class 0.000 claims abstract description 8
- 239000006227 byproduct Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 230000035484 reaction time Effects 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 65
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 239000002904 solvent Substances 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 150000001298 alcohols Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 112
- 238000000926 separation method Methods 0.000 description 46
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 36
- ALHUXMDEZNLFTA-UHFFFAOYSA-N 2-methylquinoxaline Chemical class C1=CC=CC2=NC(C)=CN=C21 ALHUXMDEZNLFTA-UHFFFAOYSA-N 0.000 description 30
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 235000019445 benzyl alcohol Nutrition 0.000 description 24
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 16
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical class C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 4
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 4
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- AVPVRXORILGHNM-UHFFFAOYSA-N chlorobenzene;methanol Chemical class OC.ClC1=CC=CC=C1 AVPVRXORILGHNM-UHFFFAOYSA-N 0.000 description 4
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 4
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical class CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical class OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- MFGWMAAZYZSWMY-UHFFFAOYSA-N (2-naphthyl)methanol Chemical compound C1=CC=CC2=CC(CO)=CC=C21 MFGWMAAZYZSWMY-UHFFFAOYSA-N 0.000 description 2
- 0 *c1ccccc1 Chemical compound *c1ccccc1 0.000 description 2
- DXYYSGDWQCSKKO-UHFFFAOYSA-N 2-methylbenzothiazole Chemical class C1=CC=C2SC(C)=NC2=C1 DXYYSGDWQCSKKO-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical class OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 2
- LVILGAOSPDLNRM-UHFFFAOYSA-N 4-methylpyrimidine Chemical class CC1=CC=NC=N1 LVILGAOSPDLNRM-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 150000003577 thiophenes Chemical class 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
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- PBLNHHSDYFYZNC-UHFFFAOYSA-N (1-naphthyl)methanol Chemical compound C1=CC=C2C(CO)=CC=CC2=C1 PBLNHHSDYFYZNC-UHFFFAOYSA-N 0.000 description 1
- FSWNRRSWFBXQCL-UHFFFAOYSA-N (3-bromophenyl)methanol Chemical compound OCC1=CC=CC(Br)=C1 FSWNRRSWFBXQCL-UHFFFAOYSA-N 0.000 description 1
- XGQBTFOINCGEAU-UHFFFAOYSA-N 1-(2-bromoprop-2-enyl)-2-phenylbenzimidazole Chemical compound N=1C2=CC=CC=C2N(CC(=C)Br)C=1C1=CC=CC=C1 XGQBTFOINCGEAU-UHFFFAOYSA-N 0.000 description 1
- LQWPAMNCTNMMDB-UHFFFAOYSA-N 2-(2-phenylethyl)pyrazine Chemical class C=1C=CC=CC=1CCC1=CN=CC=N1 LQWPAMNCTNMMDB-UHFFFAOYSA-N 0.000 description 1
- NIJWAAUHTPDGOM-UHFFFAOYSA-N 2-(2-phenylethyl)pyridine Chemical class C=1C=CC=CC=1CCC1=CC=CC=N1 NIJWAAUHTPDGOM-UHFFFAOYSA-N 0.000 description 1
- OKKXXGHSFMJXRJ-UHFFFAOYSA-N 2-(2-phenylethyl)quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1CCC1=CC=CC=C1 OKKXXGHSFMJXRJ-UHFFFAOYSA-N 0.000 description 1
- IOEDTNCBXNRXEN-UHFFFAOYSA-N 2-(2-phenylethyl)quinoxaline Chemical class C=1N=C2C=CC=CC2=NC=1CCC1=CC=CC=C1 IOEDTNCBXNRXEN-UHFFFAOYSA-N 0.000 description 1
- QIFFJQLZSVOEHJ-UHFFFAOYSA-N 2-nonylquinoxaline Chemical class C(CCCCCCCC)C1=NC2=CC=CC=C2N=C1 QIFFJQLZSVOEHJ-UHFFFAOYSA-N 0.000 description 1
- XNFBYJYNDKPWIJ-UHFFFAOYSA-N 2-pentylquinoxaline Chemical class C1=CC=CC2=NC(CCCCC)=CN=C21 XNFBYJYNDKPWIJ-UHFFFAOYSA-N 0.000 description 1
- AWSXJRCYZQPTSD-UHFFFAOYSA-N 4-(2-phenylethyl)pyrimidine Chemical class C=1C=CC=CC=1CCC1=CC=NC=N1 AWSXJRCYZQPTSD-UHFFFAOYSA-N 0.000 description 1
- JGKNJZAKXAUUAO-UHFFFAOYSA-N Cc1cc(C=[F])c(C=[IH])cc1 Chemical compound Cc1cc(C=[F])c(C=[IH])cc1 JGKNJZAKXAUUAO-UHFFFAOYSA-N 0.000 description 1
- GAEQWKVGMHUUKO-UHFFFAOYSA-N Girinimbine Chemical compound C1=CC(C)(C)OC2=C1C(NC1=CC=CC=C11)=C1C=C2C GAEQWKVGMHUUKO-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种杂环甲基化合物的脱水C‑烷基化方法,以醇为烷基化试剂、与杂环甲基化合物在无需催化剂存在下进行脱水C‑烷基化反应合成烷基化的杂环化合物,且醇与杂环甲基化合物可在空气和碱存在下直接对甲基位进行脱水C‑烷基化反应,反应温度为100~180℃,反应时间为6~60小时,反应的溶剂为有机溶剂,副产物为水。该方法使用廉价易得、来源广泛、稳定低毒的醇类为烷基化试剂,不使用催化剂,在空气与碱的存在下,经脱水C‑烷基化反应直接合成烷基化的杂环化合物。对反应条件的要求较低,具有较广的适用范围,也应具有一定的研究和工业应用前景。
Description
技术领域
本发明涉及化学合成技术领域,具体涉及一种杂环甲基化合物的脱水C-烷基化方法。
背景技术
喹啉等杂环结构大量存在于天然产物、农药化合物和药理活性化合物中。在杂环上导入烷基结构是对杂环进行改良改性的重要手段,其中可通过杂环甲基化合物的烷基化反应来导入不同需求的基团。
传统的杂环甲基化合物的烷基化方法,首先用碱将杂环甲基转化为亲核性的亚甲基,然后与卤代烃反应。但是该方法需使用大量强碱,并使用活性高、毒性高的卤代烃,生成盐副产物,原子经济性低,也造成很大的污染。近年有文献报道了过渡金属催化下,使用醇为烷基化试剂的新方法,但是这些方法需使用价格昂贵、不易得、且对空气敏感的贵重过渡金属及配体,并在无氧条件下进行,还存在重金属在产物中的残留问题,有待改进。
因此,寻找一种更好的新方法实现杂环甲基化合物的脱水C-烷基化合成烷基取代的杂环化合物对有机合成、生化和药物化学家而言都是非常有意义的研究。
发明内容
针对现有技术存在的不足,本发明的目的在于提供一种杂环甲基化合物的脱水C-烷基化方法,该方法以绿色的醇为烷基化试剂、与杂环甲基化合物在无需过渡金属催化剂存在下进行脱水C-烷基化反应合成烷基化的杂环化合物的新方法。
为实现上述目的,本发明提供了如下技术方案:一种杂环甲基化合物的脱水C-烷基化方法,以醇为烷基化试剂、与杂环甲基化合物在无需催化剂存在下进行脱水C-烷基化反应合成烷基化的杂环化合物,且醇与杂环甲基化合物可在空气和碱存在下直接对甲基位进行脱水C-烷基化反应,反应温度为100~180℃,反应时间为6~60小时,反应的溶剂为有机溶剂,副产物为水,反应式为:
上式中:R1可以是各种官能团取代在2-,3-或4-的苯基或是取代呋喃、取代噻吩、取代吡啶等各类取代杂芳基或是各种碳链长度和支链取代的烷基;
R2是氢或是甲基、乙基等烷基或是取代烷基、卤素原子、烷氧基等从简单到复杂的各种取代基或是在芳环上的N、O、S等杂原子或是无取代和取代的苯并杂环体系。
本发明的反应,无需使用过渡金属催化剂或其它催化剂。
作为优选是,本发明所述碱的用量为10~200mol%,所述碱的最佳用量为50-100mol%。且碱为Cs2CO3、K2CO3、Na2CO3、Li2CO3、KHCO3、NaHCO3、CH3COOK、K3PO4·3H2O、LiOH、NaOH、KOH、CsOH、LiOtBu、NaOtBu、KOtBu、或CsOtBu等。
作为优选的,本发明反应的溶剂可以是各种有机溶剂,优选为甲苯或二甲苯。
作为优选的,本发明反应温度采用120-160℃,反应时间为12-48小时。反应在空气下进行,空气对反应有促进作用。
本发明所使用的醇、碱和杂环甲基化合物普遍商品化,可以直接从现有市场上购买得到。
本发明的优点是:与现有技术相比,本发明方法可使用廉价易得、来源广泛、稳定低毒、绿色的醇类化合物为烷基化试剂,不使用任何过渡金属催化剂和配体,反应无需惰性气体保护,可在空气下直接进行,易于操作,副产物为水,绿色环保无污染。因此,本发明方法对反应条件的要求较低、适用范围较广,与已知方法相比优势明显,价格便宜、简单易得,具有潜在广泛的应用前景。
下面结合说明书具体实施例对本发明作进一步说明。
具体实施方式
本发明旨在开发一种以绿色的醇为烷基化试剂、与杂环甲基化合物在无需过渡金属催化剂存在下进行脱水C-烷基化反应合成烷基化的杂环化合物的新方法。通过下述实施方式将有助于理解本发明,但并不限制于本发明的内容。
实施例1
2-甲基喹啉和苯甲醇反应制备2-苯乙基喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),苯甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率88%。1H NMR(300MHz,CDCl3):δ8.12(d,J=8.4Hz,1H),8.04(d,J=8.4 Hz,1H),7.79(d,J=8.1Hz,1H),7.75-7.70(m,1H),7.54-7.49(m,1H),7.34-7.22(m,6H),3.35-3.30(m,2H),3.21-3.16(m,2H).13C NMR(125.4MHz,CDCl3):δ161.7,147.9,141.4,136.1,129.3,128.8,128.4,128.3,127.4,126.7,125.9,125.7,121.5,40.9,35.8。
实施例2
2-甲基喹啉和4-甲基苯甲醇反应制备2-(4-甲基苯乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),4-甲基苯甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率70%。1H NMR(500MHz,CDCl3):δ8.07(d,J=8.5Hz,1H),8.03(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.70-7.67(m,1H),7.50-7.47(m,1H),7.22(d,J=8.5Hz,1H),7.14(d,J=8.0Hz,2H),7.09(d,J=8.0Hz,2H),3.28-3.25(m,2H),3.13-3.09(m,2H),2.31(s,3H).13C NMR(125.4MHz,CDCl3):δ161.9,147.9,138.4,136.1,135.4,129.3,129.0,128.8,128.3,127.5,126.8,125.8,121.5,41.1,35.5,21.0。
实施例3
2-甲基喹啉和4-甲氧基苯甲醇反应制备2-(4-甲氧基苯乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),4-甲氧基苯甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率65%。1H NMR(300MHz,CDCl3):δ8.10(d,J=8.4Hz,1H),8.03(d,J=8.4Hz,1H),7.77(d,J=8.4Hz,1H),7.73-7.67(m,1H),7.52-7.47(m,1H),7.23-7.15(m,3H),6.83(d,J=8.4Hz,2H),3.78(s,3H),3.30-3.25(m,2H),3.14-3.09(m,2H).13C NMR(125.4MHz,CDCl3):δ161.8,157.8,147.9,136.1,133.5,129.33,129.28,128.8,127.4,126.7,125.7,121.5,113.7,55.1,41.1,35.0。
实施例4
2-甲基喹啉和3-甲氧基苯甲醇反应制备2-(3-甲氧基苯乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),3-甲氧基苯甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率85%。1H NMR(500MHz,CDCl3):δ8.07(d,J=8.5Hz,1H),8.03(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.71-7.67(m,1H),7.50-7.47(m,1H),7.24-7.18(m,2H),6.84(d,J=7.5Hz,1H),6.81(s,1H),6.75-6.73(m,1H),3.75(s,3H),3.29-3.27(m,2H),3.15-3.12(m,2H).13C NMR(125.4MHz,CDCl3):δ161.7,159.6,147.9,143.1,136.2,129.4,129.3,128.8,127.5,126.8,125.7,121.5,120.9,114.1,111.5,55.1,40.8,35.9。
实施例5
2-甲基喹啉和2-甲氧基苯甲醇反应制备2-(2-甲氧基苯乙基)喹啉
20mL反应管中依次加入2-甲基喹啉(0.5mmol),2-甲氧基苯甲醇(1mmol,2equiv.),CsOH(150mol%),0.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率76%。1H NMR(500MHz,CDCl3):δ8.06(dd,J=8.5Hz,2H),7.78(d,J=8.0Hz,1H),7.71-7.68(m,1H),7.51-7.48(m,1H),7.27(b,1H),7.22-7.19(m,1H),7.15(d,J=7.0Hz,1H),6.88-6.85(m,2H),3.83(s,3H),3.28-3.25(m,2H),3.15-3.12(m,2H).13CNMR(125.4MHz,CDCl3):δ162.6,157.5,147.9,136.1,130.0,129.9,129.3,128.9,127.5,127.3,126.8,125.7,121.7,120.4,110.2,55.3,39.3,30.7.HRMS Calcd for[C18H17NO+H]+:264.1383;found:264.1389。
实施例6
2-甲基喹啉和3-氯苯甲醇反应制备2-(3-氯苯乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),3-氯苯甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率75%。1H NMR(500MHz,CDCl3):δ8.07(d,J=8.5Hz,1H),8.02(d,J=8.5Hz,1H),7.76(d,J=8.0Hz,1H),7.70-7.67(m,1H),7.50-7.46(m,1H),7.25(b,1H),7.20-7.15(m,3H),7.10-7.09(m,1H),3.27-3.24(m,2H),3.14-3.11(m,2H).13C NMR(125.4MHz,CDCl3):δ161.1,147.9,143.5,136.2,134.1,129.6,129.4,128.8,128.6,127.5,126.8,126.7,126.1,125.8,121.4,40.5,35.3.HRMS Calcd for[C17H14ClN+H]+:268.0888;found:268.0899。
实施例7
2-甲基喹啉和3-吡啶甲醇反应制备2-(2-(3-吡啶)乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),3-吡啶甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率92%。1H NMR(500MHz,CDCl3):δ8.37(s,1H),8.29(d,J=3.5Hz,1H),7.94(d,J=8.5Hz,1H),7.86(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.55-7.52(m,1H),7.37-7.31(m,1H),7.03-6.99(m,2H),3.14-3.11(m,2H),3.04-3.01(m,2H).13C NMR(125.4MHz,CDCl3):δ160.4,149.7,147.7,147.2,136.5,135.9,135.6,129.1,128.6,127.2,126.5,125.6,122.9,121.1,39.8,32.2。
实施例8
2-甲基喹啉和2-吡啶甲醇反应制备2-(2-(2-吡啶)乙基)喹啉
100mL反应管中依次加入2-甲基喹啉(2mmol),2-吡啶甲醇(4mmol,2equiv.),CsOH(50mol%),2mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率80%。1H NMR(500MHz,CDCl3):δ8.55(d,J=5.0Hz,1H),8.06(d,J=8.5Hz,1H),7.99(d,J=8.5Hz,1H),7.73(d,J=8.5Hz,1H),7.67-7.64(m,1H),7.52-7.49(m,1H),7.46-7.43(m,1H),7.35(d,J=8.5Hz,1H),7.14(d,J=7.5Hz,1H),7.08-7.05(m,1H),3.45-3.42(m,2H),3.36-3.32(m,2H).13C NMR(125.4MHz,CDCl3):δ161.5,160.9,149.1,147.8,136.1,136.0,129.1,128.7,127.3,126.6,125.6,122.9,121.4,121.0,38.6,37.8。
实施例9
2-甲基喹喔啉和苯甲醇反应制备2-苯乙基喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率83%。1H NMR(300MHz,CDCl3):δ8.63(s,1H),8.08(d,J=8.7Hz,2H),7.79-7.70(m,2H),7.32-7.19(m,5H),3.37-3.32(m,2H),3.22-3.17(m,2H).13C NMR(125.4MHz,CDCl3):δ156.4,145.8,142.2,141.2,140.7,129.9,129.2,129.0,128.9,128.5,128.4,126.2,38.1,35.2。
实施例10
2-甲基喹喔啉和4-甲基苯甲醇反应制备2-(4-甲基苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),4-甲基苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率86。1HNMR(300MHz,CDCl3):δ8.61(s,1H),8.07(dd,J=2.1Hz,J=7.8Hz,2H),7.78-7.67(m,2H),7.13-7.07(m,4H),3.37-3.28(m,2H),3.17-3.12(m,2H),2.31(s,1H).13C NMR(125.4MHz,CDCl3):δ156.6,145.8,142.3,141.3,137.7,135.7,129.9,129.2(2C),129.0,128.9,128.3,38.2,34.9,21.0.HRMS Calcd for[C17H16N2+H]+:249.1386;found:249.1394。
实施例11
2-甲基喹喔啉和4-甲氧基苯甲醇反应制备2-(4-甲氧基苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),4-甲氧基苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率91%。1H NMR(300MHz,CDCl3):δ8.61(s,1H),8.08(d,J=2.1Hz,1H),8.06(d,J=2.1Hz,1H),7.79-7.68(m,2H),7.14(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,2H),3.78(s,3H),3.30-3.28(m,2H),3.15-3.10(m,2H).13C NMR(125.4MHz,CDCl3):δ158.1,156.6,145.8,142.3,141.3,132.8,129.9,129.4,129.2,129.0,128.9,114.0,55.2,38.4,34.4.HRMS Calcd for[C17H16N2O+H]+:265.1335;found:265.1353。
实施例12
2-甲基喹喔啉和3-甲氧基苯甲醇反应制备2-(3-甲氧基苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),3-甲氧基苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率80%。1H NMR(300MHz,CDCl3):δ8.64(s,1H),8.09-8.06(m,2H),7.79-7.68(m,2H),7.23-7.18(m,1H),6.83-6.74(m,3H),3.76(s,3H),3.36-3.31(m,2H),3.19-3.14(m,2H).13C NMR(125.4MHz,CDCl3):δ159.8,156.4,145.8,142.4,142.3,141.3,130.0,129.5,129.2,129.1,128.9,120.8,114.3,111.7,55.1,38.0,35.2.HRMS Calcd for[C17H16N2O+H]+:265.1335;found:265.1354。
实施例13
2-甲基喹喔啉和2-甲氧基苯甲醇反应制备2-(2-甲氧基苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),2-甲氧基苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率79%。1H NMR(300MHz,CDCl3):δ8.63(s,1H),8.07(dd,J=2.1Hz,J=7.8Hz,2H),7.78-7.67(m,2H),7.23-7.11(m,2H),6.88-6.83(m,2H),3.77(s,3H),3.34-3.28(m,2H),3.19-3.14(m,2H).13C NMR(125.4MHz,CDCl3):δ157.5,157.2,146.1,142.2,141.2,130.1,129.8,129.2,129.1,128.92,128.86,127.6,120.5,110.3,55.2,36.6,30.2.HRMS Calcd for[C17H16N2O+H]+:265.1335;found:265.1353。
实施例14
2-甲基喹喔啉和3-氯苯甲醇反应制备2-(3-氯苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),3-氯苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率80%。1H MR(300MHz,CDCl3):δ8.64(s,1H),8.09-8.05(m,2H),7.78-7.69(m,2H),7.27-7.16(m,3H),7.12-7.08(m,1H),3.34-3.29(m,2H),3.19-3.14(m,2H).13C NMR(125.4MHz,CDCl3):δ155.9,145.6,142.9,142.3,141.4,134.3,130.0,129.8,129.24,129.15,128.9,128.6,126.7,126.5,37.6,34.6.HRMS Calcd for[C16H13ClN2+H]+:269.0840;found:269.0850。
实例15
2-甲基喹喔啉和3-溴苯甲醇反应制备2-(3-溴苯乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),3-溴苯甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率64%。1H NMR(300MHz,CDCl3):δ8.65(s,1H),8.10-8.05(m,2H),7.80-7.69(m,2H),7.43(b,1H),7.37-7.31(m,1H),7.15-7.13(m,2H),3.35-3.29(m,2H),3.19-3.14(m,2H).13C NMR(125.4MHz,CDCl3):δ155.9,145.6,143.2,142.3,141.4,131.6,130.08,130.05,129.4,129.3,129.2,128.9,127.1,122.6,37.7,34.6.HRMS Calcd for[C16H13BrN2+H]+:313.0335;found:313.0358。
实施例16
2-甲基喹喔啉和1-萘甲醇反应制备2-(2-(1-萘)乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),1-萘甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率67%。1H NMR(500MHz,CDCl3):δ8.59(s,1H),8.16(d,J=8.5Hz,1H),8.13-8.08(m,2H),7.89(d,J=8.0Hz,1H),7.81-7.22(m,3H),7.57-7.49(m,2H),7.39-7.31(m,2H),3.68-3.65(m,2H),3.49-3.46(m,2H).13C NMR(125.4MHz,CDCl3):δ156.6,145.8,142.4,141.4,136.9,134.0,131.7,130.0,129.3,129.1,128.98,128.95,127.2,126.3,126.1,125.63,125.57,123.6,37.3,32.4.HRMS Calcd for[C20H16N2+H]+:285.1386;found:285.1402。
实施例17
2-甲基喹喔啉和2-萘甲醇反应制备2-(2-(2-萘)乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),2-萘甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率82%。1H NMR(300MHz,CDCl3):δ8.64(s,1H),8.10-8.05(m,2H),7.80-7.66(m,6H),7.46-7.35(m,3H),3.44-3.38(m,2H),3.36-3.30(m,2H).13C NMR(125.4MHz,CDCl3):δ156.4,145.8,142.3,141.3,138.3,133.6,132.2,130.0,129.2,129.1,128.9,128.2,127.6,127.5,127.1,126.6,126.0,125.4,38.0,35.3.HRMS Calcd for[C20H16N2+H]+:285.1386;found:285.1385。
实施例18
2-甲基喹喔啉和2-吡啶甲醇反应制备2-(2-(2-吡啶)乙基)喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),2-吡啶甲醇(1mmol,2equiv.),KOH(100mol%),1mL甲苯,直接在空气下密封加热到140℃反应12h。产物用柱色谱分离提纯,分离收率81%。1H NMR(300MHz,CDCl3):δ8.70(s,1H),8.57-8.55(m,1H),8.08-8.04(m,2H),7.78-7.68(m,2H),7.59-7.53(m,1H),7.17-7.10(m,2H),3.54-3.47(m,2H),3.42-3.35(m,2H).13C NMR(125.4MHz,CDCl3):δ160.3,156.5,149.4,146.0,142.3,141.3,136.4,129.9,129.2,129.0,128.9,123.1,121.4,37.1,35.7.HRMS Calcd for[C15H13N3+H]+:236.1182;found:236.1190。
实施例19
2-甲基喹喔啉和正丁醇反应制备2-戊基喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),正丁醇(1mmol,2equiv.),KOH(150mol%),1.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率36%。1H NMR(500MHz,CDCl3):δ8.75(s,1H),8.09-8.04(m,2H),7.76-7.69(m,2H),3.01(t,J=7.8Hz,2H),1.89-1.83(m,2H),1.45-1.35(m,4H),0.91(t,J=7.0Hz,3H).13CNMR(125.4MHz,CDCl3):δ157.7,145.9,142.2,141.2,129.9,129.2,128.9(2C),36.5,31.6,29.2,22.5,14.0.HRMSCalcd for[C13H16N2+H]+:201.1386;found:201.1386。
实施例20
2-甲基喹喔啉和正庚醇反应制备2-辛基喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),正庚醇(1mmol,2equiv.),KOH(150mol%),1.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率60%。1H NMR(500MHz,CDCl3):δ8.75(s,1H),8.09-8.04(m,2H),7.76-7.69(m,2H),3.01(t,J=7.8Hz,2H),1.88-1.82(m,2H),1.46-1.40(m,2H),1.37-1.34(m,2H),1.32-1.27(m,6H),0.87(t,J=6.8Hz,3H).13C NMR(125.4MHz,CDCl3):δ157.7,145.8,142.2,141.2,129.9,129.2,128.9(2C),36.6,31.8,29.6,29.5,29.4,29.2,22.6,14.1.HRMS Calcd for[C16H22N2+H]+:243.1856;found:243.1853。
实施例21
2-甲基喹喔啉和正辛醇反应制备2-壬基喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),正辛醇(1mmol,2equiv.),KOH(150mol%),1.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率61%。1H NMR(500MHz,CDCl3):δ8.75(s,1H),8.09-8.04(m,2H),7.77-7.69(m,2H),3.01(t,J=7.8Hz,2H),1.88-1.82(m,2H),1.46-1.40(m,2H),1.37-1.33(m,2H),1.32-1.26(m,8H),0.87(t,J=7.0Hz,3H).13CNMR(125.4MHz,CDCl3):δ157.8,145.9,142.3,141.2,129.9,129.2,128.9(2C),36.6,31.9,29.6,29.48,29.47,29.4,29.3,22.7,14.1.HRMSCalcd for[C17H24N2+H]+:257.2012;found:257.2028。
实施例22
2-甲基喹喔啉和正十二醇反应制备2-十三基喹喔啉
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),正十二醇(1mmol,2equiv.),KOH(150mol%),1.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率52%。1H NMR(500MHz,CDCl3):δ8.75(s,1H),8.09-8.04(m,2H),7.76-7.69(m,2H),3.01(t,J=7.8Hz,2H),1.88-1.82(m,2H),1.46-1.40(m,2H),1.37-1.32(m,2H),1.29-1.25(m,18H),0.88(t,J=7.0Hz,3H).13C NMR(125.4MHz,CDCl3):δ157.7,145.8,142.2,141.2,129.9,129.2,128.9(2C),36.6,31.9,29.7,29.64(2C),29.61,29.6,29.5,29.46,29.44,29.4,22.7,14.1.HRMS Calcd for[C21H32N2+H]+:313.2638;found:313.2650。
实施例23
2-甲基喹喔啉和二苯甲醇反应制备
20mL反应管中依次加入2-甲基喹喔啉(0.5mmol),二苯甲醇(1mmol,2equiv.),CsOH(100mol%),1.5mL甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率49%。1H NMR(500MHz,CDCl3):δ8.4(s,1H),8.05-7.99(m,2H),7.74-7.66(m,2H),7.28-7.23(m,8H),7.17-7.14(m,2H),7.72(t,J=8.0Hz,1H),3.75(d,J=8.0Hz,2H).13CNMR(125.4MHz,CDCl3):δ155.5,146.0,143.6,142.3,141.1,129.9,129.2,129.1,128.9,128.6,127.9,126.5,50.9,42.3.HRMS Calcd for[C22H18N2+H]+:311.1543;found:311.1547。
实施例24
2-甲基吡嗪和苯甲醇反应制备2-苯乙基吡嗪
100mL反应管中依次加入2-甲基吡嗪(2mmol),苯甲醇(4mmol,2equiv.),CsOH(50mol%),2.0mL甲苯,直接在空气下密封加热到120℃反应24h。产物用柱色谱分离提纯,分离收率60%。1H NMR(500MHz,CDCl3):δ8.49(d,J=1.5Hz,1H),8.37(d,J=2.0Hz,1H),8.34(s,1H),7.28-7.25(m,2H),7.19-7.15(m,3H),3.13-3.09(m,2H),3.07-3.04(m,2H).13CNMR(125.4MHz,CDCl3):δ156.6,144.5,143.9,142.1,140.6,128.3,128.2,126.1,37.0,35.2.This compound was known:Lautens,M.;Roy,A.;Fukuoka,K;Fagnou,K.;Martín-Matute,B.J.Am.Chem.Soc.2001,123,5358-5359。
实施例25
2-甲基吡嗪和4-甲基苯甲醇反应制备2-(4-甲基苯乙基)吡嗪
100mL反应管中依次加入2-甲基吡嗪(2mmol),4-甲基苯甲醇(4mmol,2equiv.),CsOH(50mol%),2.0mL甲苯,直接在空气下密封加热到120℃反应24h。产物用柱色谱分离提纯,分离收率76%。1H NMR(500MHz,CDCl3):δ8.51-8.57(m,1H),8.38(d,J=2.5Hz,1H),8.34(d,J=1.0Hz,1H),7.09-7.05(m,4H),3.11-3.08(m,2H),3.04-3.01(m,2H),2.31(s,3H).13CNMR(125.4MHz,CDCl3):δ156.8,144.6,144.0,142.2,137.6,135.6,129.1,128.2,126.8,37.3,34.9,20.9。
实施例26
4-甲基嘧啶和苯甲醇反应制备4-苯乙基嘧啶
20mL反应管中依次加入4-甲基嘧啶(0.5mmol),苯甲醇(1mmol,2equiv.),KOH(100mol%),1.0mL甲苯,直接在空气下密封加热到120℃反应12h。产物用柱色谱分离提纯,分离收率66%。1H NMR(500MHz,CDCl3):δ8.15(d,J=1.0Hz,1H),8.56(d,J=5.0Hz,1H),7.29-7.26(m,2H),7.21-7.17(m,3H),7.07(dd,J=1.5Hz,J=5.0Hz,1H),3.07(s,4H).13CNMR (125.4MHz,CDCl3):δ169.5,158.7,156.6,140.5,128.4,128.3,126.2,120.6,39.4,34.6。
实施例27
2-甲基苯并噻唑和苯甲醇反应制备4-苯乙基苯并噻唑
20mL反应管中依次加入2-甲基苯并噻唑(0.5mmol),苯甲醇(1mmol,2equiv.),CsOH(100mol%),1.5mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率43%。1H NMR(500MHz,CDCl3):δ7.98(d,J=8.0Hz,1H),7.85-7.83(m,1H),7.48-7.45(m,1H),7.38-7.34(m,1H),7.33-7.28(m,3H),7.25-7.22(m,2H),3.45-3.42(m,2H),3.23-3.20(m,2H).13CNMR(125.4MHz,CDCl3):δ171.0,153.2,140.2,135.1,128.6,128.5,126.5,126.0,124.8,122.6,121.5,36.0,35.6。
实施例28
2-甲基吡啶和苯甲醇反应制备2-苯乙基吡啶
20mL反应管中依次加入2-甲基吡啶(0.5mmol),苯甲醇(1mmol,2equiv.),CsOH(100mol%),1.0mL二甲苯,直接在空气下密封加热到160℃反应24h。产物用柱色谱分离提纯,分离收率45%。1H NMR(500MHz,CDCl3):δ8.56(d,J=5.0Hz,1H),7.57-7.54(m,1H),7.29-7.26(m,2H),7.21-7.17(m,3H),7.33-7.28(m,3H),7.12-7.10(m,1H),7.07(d,J=8.0Hz,1H),3.11-3.08(m,2H),3.07-3.03(m,2H).13C NMR(125.4MHz,CDCl3):δ161.2,149.3,141.6,136.3,128.5,128.4,126.0,123.0,121.2,40.3,36.1。
本发明以醇为烷基化试剂、与杂环甲基化合物在无需催化剂存在下进行脱水C-烷基化反应合成烷基化的杂环化合物,且醇与杂环甲基化合物可在空气和碱存在下直接对甲基位进行脱水C-烷基化反应,反应温度为100~180℃,反应时间为6~60小时,反应的溶剂为有机溶剂,副产物为水,反应式为:
上式中:R1可以是各种官能团取代在2-,3-或4-的苯基或是取代呋喃、取代噻吩、取代吡啶等各类取代杂芳基或是各种碳链长度和支链取代的烷基;
R2是氢或是甲基、乙基等烷基或是取代烷基、卤素原子、烷氧基等从简单到复杂的各种取代基或是在芳环上的N、O、S等杂原子或是无取代和取代的苯并杂环体系。
本发明的反应,无需使用过渡金属催化剂或其它催化剂。
本发明所述碱的用量为10~200mol%,所述碱的最佳用量为50-100mol%。且碱为Cs2CO3、K2CO3、Na2CO3、Li2CO3、KHCO3、NaHCO3、CH3COOK、K3PO4·3H2O、LiOH、NaOH、KOH、CsOH、LiOtBu、NaOtBu、KOtBu、或CsOtBu等。
本发明反应的溶剂可以是各种有机溶剂,优选为甲苯或二甲苯。
本发明反应温度最佳为120-160℃,反应时间最佳为12-48小时。反应在空气下进行,空气对反应有促进作用。
本发明方法可使用廉价易得、来源广泛、稳定低毒、绿色的醇类化合物为烷基化试剂,不使用任何过渡金属催化剂和配体,反应无需惰性气体保护,可在空气下直接进行,易于操作,副产物为水,绿色环保无污染。因此,本发明方法对反应条件的要求较低、适用范围较广,与已知方法相比优势明显,价格便宜、简单易得,具有潜在广泛的应用前景。
上述实施例对本发明的具体描述,只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限定,本领域的技术工程师根据上述发明的内容对本发明作出一些非本质的改进和调整均落入本发明的保护范围之内。
Claims (3)
1.一种杂环甲基化合物的脱水C-烷基化方法,其特征在于:以醇为烷基化试剂、在空气和碱的存在下、无需其他催化剂参与下,醇与氮杂环甲基化合物在氮杂环甲基化合物的甲基位进行脱水C-烷基化反应可合成得到烷基化的杂环化合物,反应温度为100~180℃,反应时间为6~60小时,反应溶剂为有机溶剂,副产物为水,反应式为:
上式中:R1选自各种官能团取代在2-、3-或4-的苯基或各类取代杂芳基或各种直链或支链的烷基;
R2是氢或是烷基或是取代烷基或是卤素原子或是烷氧基。
2.根据权利要求1所述的一种杂环甲基化合物的脱水C-烷基化方法,其特征在于:反应用的有机溶剂为甲苯或二甲苯。
3.根据权利要求1所述的一种杂环甲基化合物的脱水C-烷基化方法,其特征在于:反应温度采用120-160℃,反应时间为12-48小时。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410723220.7A CN104529889B (zh) | 2014-12-02 | 2014-12-02 | 一种杂环甲基化合物的脱水c-烷基化方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410723220.7A CN104529889B (zh) | 2014-12-02 | 2014-12-02 | 一种杂环甲基化合物的脱水c-烷基化方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104529889A CN104529889A (zh) | 2015-04-22 |
CN104529889B true CN104529889B (zh) | 2018-09-04 |
Family
ID=52845569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410723220.7A Expired - Fee Related CN104529889B (zh) | 2014-12-02 | 2014-12-02 | 一种杂环甲基化合物的脱水c-烷基化方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104529889B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107188909B (zh) * | 2017-06-13 | 2020-03-10 | 青岛农业大学 | 一种合成吲哚取代或二茂铁取代氮杂芳烃的方法 |
CN111253305B (zh) * | 2018-11-30 | 2022-09-02 | 中国科学院大连化学物理研究所 | 一种烷基取代氮杂芳烃的烯基化或烷基化反应方法 |
CN112300085A (zh) * | 2020-11-17 | 2021-02-02 | 温州大学 | 一种甲基杂环化合物的烯基化方法 |
CN113087673B (zh) * | 2021-04-07 | 2023-02-28 | 河南农业大学 | 一种烷基/烯基取代含氮杂环化合物的制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008092863A2 (en) * | 2007-01-29 | 2008-08-07 | Hans Kan | Collapsible bed structure and luggage incorporating same |
CN102627517A (zh) * | 2012-03-23 | 2012-08-08 | 温州大学 | 一种仲醇的β-烷基化方法 |
CN103145643A (zh) * | 2013-03-19 | 2013-06-12 | 温州大学 | 一种氨基噻唑化合物的脱水烷基化方法 |
CN103288722A (zh) * | 2013-05-08 | 2013-09-11 | 温州大学 | 一种仲胺的高选择性合成方法 |
CN103864624A (zh) * | 2014-03-05 | 2014-06-18 | 湖北大学 | 一种简单碱催化的n-烷基化高效制备仲胺的方法 |
-
2014
- 2014-12-02 CN CN201410723220.7A patent/CN104529889B/zh not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008092863A2 (en) * | 2007-01-29 | 2008-08-07 | Hans Kan | Collapsible bed structure and luggage incorporating same |
CN102627517A (zh) * | 2012-03-23 | 2012-08-08 | 温州大学 | 一种仲醇的β-烷基化方法 |
CN103145643A (zh) * | 2013-03-19 | 2013-06-12 | 温州大学 | 一种氨基噻唑化合物的脱水烷基化方法 |
CN103288722A (zh) * | 2013-05-08 | 2013-09-11 | 温州大学 | 一种仲胺的高选择性合成方法 |
CN103864624A (zh) * | 2014-03-05 | 2014-06-18 | 湖北大学 | 一种简单碱催化的n-烷基化高效制备仲胺的方法 |
Non-Patent Citations (3)
Title |
---|
Alkylation of 2-methyl quinoline with alcohols under additive-free conditions by Al2O3-supported Pt catalyst;Chandan Chaudhari et al;《Tetrahedron Letters》;20130925;第54卷;第6490–6493页,第6492页图3 * |
Iridium-Catalyzed Alkylation of Methylquinolines with Alcohols;Yasushi Obora et al;《TheJournal of Organic Chemistry》;20120926;第77卷;第9429−9433页 * |
过渡金属催化醇与胺有氧脱水反应及相关研究进展;徐清,***;《有机化学》;20121008;第33卷;第18-35页 * |
Also Published As
Publication number | Publication date |
---|---|
CN104529889A (zh) | 2015-04-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104529889B (zh) | 一种杂环甲基化合物的脱水c-烷基化方法 | |
Wang et al. | An improved Ullmann–Ukita–Buchwald–Li conditions for CuI-catalyzed coupling reaction of 2-pyridones with aryl halides | |
CN108689895B (zh) | 一种硫代酰胺衍生物及其制备方法 | |
CN104557800A (zh) | 2-苯氧基四氢呋(吡)喃衍生物及其在五氟磺草胺合成中的应用 | |
CN105884570A (zh) | 含氟二芳基碘盐及其用途 | |
CN109293491B (zh) | 一种芳基重氮盐脱重氮上酰基的方法 | |
CN103848767B (zh) | 一种芳基硫醚类化合物的合成方法 | |
CN111187298B (zh) | 一种c2-膦酰基亚甲基吲哚化合物及其制备方法和用途 | |
CN110372463B (zh) | 一种硝基芳烃和硼酸化合物偶联合成磺酰胺化合物的方法 | |
CN106795191B (zh) | 用于交联反应的新的预催化剂支架及其制造和使用方法 | |
JP6530807B2 (ja) | インデノイソキノリン派生物の調製方法 | |
CN103087055B (zh) | 银催化的双杂环分子的合成及具有荧光活性的双杂环分子 | |
CN102875421A (zh) | 基于对硝基苯甲酸的氮杂环丙烷化合物开环方法 | |
CN1332944C (zh) | 氨基酸促进的CuI催化的芳基卤化物和烃基亚磺酸盐的偶联反应 | |
CN113121401B (zh) | 一种n-取代羰基氟磺酰胺化合物、制备方法及其应用 | |
CN106349182B (zh) | 4,5-二取代-2-氨基噻唑化合物的制备方法 | |
EP2886548A1 (en) | Method for producing borinic acid derivative, and novel borinic acid derivative | |
WO2016039691A1 (en) | Catalysts for making chiral heterocyclic sulfoxides | |
CN110156639B (zh) | 催化炔烃与碳化二亚胺加成反应的方法 | |
CN114213298B (zh) | 一种由硫酚直接氧化制备硫代磺酸酯类化合物的方法 | |
CN113321669B (zh) | 一种磺酰亚胺类金属盐、其制备方法及应用 | |
CN106366069A (zh) | 一种n‑杂芳基咔唑类化合物的制备方法 | |
CN106905368B (zh) | 氨基酸促进的10-芳硫基-9-氧杂-10-膦杂菲-10-氧化物的制备方法 | |
CN105541742A (zh) | 一种依泽麦布中间体的制备方法 | |
CN111484420B (zh) | 合成三芳基甲烷衍生物的方法及其所得三芳基甲烷衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: 325000 Wenzhou City National University Science Park incubator, No. 38 Dongfang South Road, Ouhai Economic Development Zone, Wenzhou, Zhejiang Applicant after: Wenzhou University Address before: 325000 Wenzhou tea mountain high education park in Zhejiang Province Applicant before: Wenzhou University |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180904 |
|
CF01 | Termination of patent right due to non-payment of annual fee |