CN114249625A - 一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法 - Google Patents
一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法 Download PDFInfo
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- -1 aryl formic acid Chemical compound 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 21
- 125000005842 heteroatom Chemical group 0.000 title abstract description 37
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title abstract description 26
- 150000004945 aromatic hydrocarbons Chemical class 0.000 title abstract description 19
- 235000019253 formic acid Nutrition 0.000 title abstract description 13
- 238000005859 coupling reaction Methods 0.000 title abstract description 10
- 229910052723 transition metal Inorganic materials 0.000 title abstract description 10
- 230000006324 decarbonylation Effects 0.000 title abstract description 9
- 238000006606 decarbonylation reaction Methods 0.000 title abstract description 9
- 150000003624 transition metals Chemical class 0.000 title abstract description 9
- 230000008878 coupling Effects 0.000 title abstract description 6
- 238000010168 coupling process Methods 0.000 title abstract description 6
- 238000006555 catalytic reaction Methods 0.000 title abstract description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 29
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims abstract description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 9
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 241001120493 Arene Species 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 claims description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims 1
- OSTMCQXLMNDQGL-UHFFFAOYSA-N 1-azanylidyne-n-nitromethanesulfonamide Chemical compound [O-][N+](=O)NS(=O)(=O)C#N OSTMCQXLMNDQGL-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 238000007069 methylation reaction Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 125000000524 functional group Chemical group 0.000 abstract description 5
- 230000011987 methylation Effects 0.000 abstract description 5
- 230000000269 nucleophilic effect Effects 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000007818 Grignard reagent Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- UYVXZUTYZGILQG-UHFFFAOYSA-N methoxyboronic acid Chemical compound COB(O)O UYVXZUTYZGILQG-UHFFFAOYSA-N 0.000 abstract description 2
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000001308 synthesis method Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 3
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- QBHDSQZASIBAAI-UHFFFAOYSA-N 4-acetylbenzoic acid Chemical compound CC(=O)C1=CC=C(C(O)=O)C=C1 QBHDSQZASIBAAI-UHFFFAOYSA-N 0.000 description 1
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001265 acyl fluorides Chemical class 0.000 description 1
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 1
- 229960002916 adapalene Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical class [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法。该方法是在惰性气体氛围下,将(杂)芳基甲酸、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应,得甲基(杂)芳烃产物。该方法以稳定且廉价易得的(杂)芳基甲酸作为原料合成甲基(杂)芳烃,可弥补传统过渡金属催化卤代(杂)芳烃与亲核性甲基化试剂的偶联反应中存在的不足,具有以下优点:(1)避免使用较昂贵且难制备的卤代(杂)芳烃,同时避免含卤废弃物的产生;(2)避免甲基格氏试剂、甲基硼酸等不稳定原料的使用,反应具有较好的官能团容忍性;(3)(杂)芳基甲酸原料与产物极性差别较大,易于通过柱层析分离。
Description
技术领域
本发明涉及一种甲基(杂)芳烃的合成方法,特征是以(杂)芳基甲酸为亲电试剂,在过渡金属催化下与三甲基环三氧硼烷进行脱羰偶联,合成甲基(杂)芳烃,属于有机合成中的领域。
背景技术
甲基是有机化合物中最基础,最广泛存在的一类非极性官能团,在化学反应中一般较为惰性。对于药物化学来说,特别是对许多生物活性分子而言,引入一个简单的甲基,会极大改变其溶解性、亲水性以及药物构象等,这也被人们称为“甲基化效应”。在目前最畅销的200种小分子药物里,有超过70%的分子中带有一个以上的甲基。同时,(杂)芳基上的甲基还可以衍生为其他官能团,如醛基、羧基、苄醇、苄卤等,因此甲基化反应在合成化学中也有着广泛的应用。
过渡金属钯或镍催化卤代(杂)芳烃与亲核性甲基化试剂的偶联反应是制备甲基(杂)芳烃最有效的方法之一,但具有以下缺点:(1)卤代(杂)芳烃需要通过较苛刻的反应条件制备,价格昂贵且易产生大量含卤废弃物;(2)亲核性甲基化试剂通常为甲基格氏试剂、甲基硼酸等高活性试剂,反应官能团容忍性较差;(3)卤代原料与甲基化产物极性相近,难以通过柱层析方法分离。
(杂)芳基甲酸类化合物是无毒、廉价、易得且具有较好稳定性的化工原料。近年来,通过将(杂)芳基甲酸预活化为酸酐、酰胺、酯类、酰氯以及酰氟等(杂)芳酰基化合物后,以过渡金属(钯、镍、铑等)催化的方法可以实现(杂)芳基甲酸与不同亲核试剂的脱羰交叉偶联反应,完成C–C、C–O、C–N、C–S等化学键的构筑。
发明内容
针对现有技术存在的缺陷,本发明的目的是在于提供一种以(杂)芳基甲酸为亲电试剂,在过渡金属催化下与温和型亲核甲基化试剂发生脱羰偶联,简洁高效地合成甲基(杂)芳烃的方法,以稳定且廉价易得的(杂)芳基甲酸作为亲电试剂合成甲基(杂)芳烃可弥补传统过渡金属催化甲基化反应存在的不足。
为实现上述目的,本发明提供了一种甲基(杂)芳烃的合成方法,该方法是在惰性气体氛围下,将Ar–COOH、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应,得Ar–CH3;其中,所述Ar为芳基或杂芳基,所述芳基或杂芳基任选地被一个或更多个如下取代基取代:烷基、芳基、酰基、硝基、醛基、氰基、三氟甲基、甲氧基、磺酰基、磺胺基、酯基、胺基。“任选地被一个或更多个如下取代基取代”是指可以被一个或更多个指定的取代基取代,也可以为非取代。
可选地,所述芳基选自苯、萘、菲、蒽、芘,所述杂芳基选自喹啉、吡啶、苯并噻吩、苯并呋喃、吲哚、噻唑、咪唑、噁唑。
在本发明的具体实施方式中,所述芳基选自苯、萘,所述杂芳基选自苯并呋喃、喹啉、噻唑。
具体地,在本发明中,所述Ar–COOH选自如下结构:
上述合成方法中,含钯催化剂是以下钯(II)化合物之一:二氯化钯(PdCl2)、醋酸钯(Pd(OAc)2)、三氟乙酸钯(Pd(TFA)2)、二(乙酰丙酮)钯(Pd(acac)2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)。
上述合成方法中,膦配体是以下膦化合物之一:双(2-二苯基膦苯基)醚(DPEPhos)、1,2-双(二苯基膦)乙烷(dppe)、1,1’-双(二苯基膦)二茂铁(dppf)、1,4-双(二苯基膦)丁烷(dppb)、4,5-双(二苯基膦)-9,9’-二甲基氧杂蒽(XantPhos)。
上述合成方法中,酸酐添加剂是以下酸酐化合物之一:包括苯甲酸酐(benzoicanhydride)、乙酸酐(Ac2O)、三氟乙酸酐(TFAA)、二碳酸二叔丁酯(Boc2O)、三甲基乙酸酐(Piv2O)。
上述合成方法中,溶剂是以下溶剂之一:THF、1,4-二氧六环、三氟甲苯、正己烷、甲苯。
上述合成方法中,含钯催化剂相对Ar–COOH的摩尔添加量为2.5%~10%,膦配体相对Ar–COOH的摩尔添加量为7.5%~30%,酸酐添加剂相对Ar–COOH的摩尔添加量为100%~300%。
在本发明的一些具体实施方式中,所述含钯催化剂相对Ar–COOH的摩尔添加量为5%;所述膦配体相对Ar–COOH的摩尔添加量为15%;所述酸酐添加剂相对Ar–COOH的摩尔添加量为150%。
上述合成方法中,Ar–COOH与三甲基环三氧硼烷的摩尔比为1:1~1:2。
上述合成方法中,脱羰偶联反应的温度为120~170℃。
上述合成方法中,脱羰偶联反应的时间为6~36小时。
上述合成方法中,反应结束后萃取溶剂为正己烷、二氯甲烷、乙醚、乙酸乙酯中的一种。
本发明所提供的合成方法为过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃,开发了一条新的甲基(杂)芳烃制备路线,其优点在于:(1)以稳定且廉价易得的(杂)芳基甲酸作为亲电试剂,避免了较为昂贵且难以制备的卤代芳烃的使用,同时避免了含卤废弃物的产生;(2)选取较为廉价稳定的三甲基环三氧硼烷作为亲核甲基化试剂,避免了甲基格氏试剂、甲基硼酸等不稳定原料的使用,反应具有较好的官能团容忍性;(3)(杂)芳基甲酸原料与产物极性差别较大,易于通过柱层析分离。
附图说明
图1所示为本发明提供的(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的合成路径图。
具体实施方式
为使本发明的上述特征、优点和目的更加简明易懂,下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了许多具体细节以便于充分理解本发明。但是本发明能以很多不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似改进,因此本发明不受下面公开的具体实施的限制。
实施例1
目标产物结构式如下:
室温下,在装有磁力搅拌子的50mL反应管中加入0.2mmol的2-萘甲酸、0.01mmol的Pd(OAc)2、0.03mmol的XantPhos,将反应管中置换为氮气后,加入0.3mmol的Piv2O、0.4mmol的三甲基环三氧硼烷以及2mL的1,4-二氧六环,将反应体系封闭后,置于带磁力搅拌的油浴加热器中,在160℃下反应24小时。反应完毕后,加入二氯甲烷萃取分离,通过柱层析得到产物。
产物为无色液体,产率为88%
1H NMR(400MHz,CDCl3)δ=2.53(s,3H),7.33(dd,J=8.4Hz,1.6,1H),7.39–7.48(m,2H),7.63(s,1H),7.75–7.78(m,2H),7.81(d,J=8.0Hz,1H)ppm.13C NMR(101MHz,CDCl3)δ=21.9,125.1,126.0,127.0,127.4,127.7,127.8,128.2,131.8,133.8,135.6ppm.
实施例2
目标产物结构式如下:
步骤同实施例1,以邻苯基苯甲酸为原料,反应时间为12小时。
产物为淡黄色液体,产率为82%。
1H NMR(400MHz,CDCl3):δ=2.27(s,3H),7.22–7.28(m,3H),7.30–7.36(m,3H),7.37–7.62(m,3H)ppm;13C NMR(100MHz,CDCl3):δ=20.6,125.9,126.9,127.3,127.4,128.2,128.9,129.3,129.9,130.4,135.5ppm.
实施例3
目标产物结构式如下:
步骤同实施例1,以邻硝基苯甲酸为原料。
产物为黄色液体,产率为84%。
1H NMR(400MHz,CDCl3):δ=2.61(s,3H),7.30–7.39(m,2H),7.50(t,J=7.6Hz,1H),7.97(d,J=8.4Hz,1H)ppm.13C NMR(100MHz,CDCl3):δ=20.6,124.8,127.0,132.9,133.1,133.7,149.5ppm.
实施例4
目标产物结构式如下:
步骤同实施例1,以对乙酰基苯甲酸为原料。
产物为无色液体,产率为81%。
1H NMR(400MHz,CDCl3):δ=2.41(s,3H),2.58(s,3H),7.26(d,J=8.8Hz,2H),7.86(d,J=8.4Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ=21.8,26.7,128.6,129.4,134.8,144.0,198.0ppm.
实施例5
目标产物结构式如下:
步骤同实施例1,以对氰基苯甲酸为原料。
产物为无色液体,产率为66%。
1H NMR(400MHz,CDCl3)δ=2.42(s,3H),7.27(d,J=7.6Hz,2H),7.54(d,J=8.4Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ=22.0,109.4,119.3,130.0,132.2,143.8ppm.
实施例6
目标产物结构式如下:
步骤同实施例1,以苯并呋喃-2-甲酸为原料,反应在170℃下进行。
产物为无色液体,产率为45%。
1H NMR(400MHz,CDCl3):δ=2.46(s,3H),6.37(p,J=1.0Hz,1H),7.15–7.23(m,2H),7.38–7.42(m,1H),7.45–7.49(m,1H)ppm;13C NMR(100MHz,CDCl3):δ=14.2,102.7,110.7,120.2,122.5,123.2,129.3,154.8,155.5ppm.
实施例7
目标产物结构式如下:
步骤同实施例1,以喹啉-6-甲酸为原料。
产物为黄色液体,产率为72%。
1H NMR(400MHz,CDCl3)δ=2.52(s,3H),7.31–7.37(m,1H),7.51–7.58(m,2H),7.99(d,J=8.4Hz,1H),8.05(d,J=8.4Hz,1H),8.83(d,J=4.4Hz,1H)ppm.13C NMR(100MHz,CDCl3)δ=21.7,121.2,126.7,128.4,129.2,131.9,135.5,136.5,147.0,149.6ppm.
实施例8
目标产物结构式如下:
步骤同实施例1,以丙磺舒为原料。
产物为无色液体,产率为64%。
1H NMR(400MHz,CDCl3)δ=0.86(td,J=7.2,1.6Hz,6H),1.49–1.58(m,4H),2.41(s,3H),3.05(td,J=7.6,1.6Hz,4H),7.23–7.32(m,2H),7.62–7.71(m,2H).13C NMR(100MHz,CDCl3)δ=11.3,21.6,22.2,50.2,127.2,129.7,137.3,143.0ppm.
实施例9
目标产物结构式如下:
步骤同实施例1,以非布索坦为原料。
产物为白色固体,产率为35%。
1H NMR(400MHz,CDCl3)δ=1.08(d,J=6.8Hz,6H),2.13–2.24(m,1H),2.36(s,3H),2.39(s,3H),3.86(d,J=6.4Hz,2H),6.96(d,J=8.8Hz,1H),7.99(d,J=8.8Hz,1H),8.04(s,1H)ppm.13C NMR(100MHz,CDCl3)δ=11.6,14.9,19.2,28.3,75.7,102.7,112.6,116.0,126.9,127.3,131.4,131.9,149.6,160.9,161.5ppm.HRMS(ESI+)calcd for C16H18N2OS[M+H]+287.1213,found 287.1209.
实施例10
目标产物结构式如下:
步骤同实施例1,以替米沙坦为原料。
产物为白色固体,产率为80%。
1H NMR(400MHz,CDCl3)δ=1.01–1.08(m,3H),1.83–1.90(m,2H),2.21(s,3H),2.77(s,3H),2.90–2.98(m,2H),3.80(s,3H),5.45(s,2H),7.10(d,J=7.6Hz,2H),7.16(d,J=7.6Hz,1H),7.19–7.25(m,4H),7.27(s,1H),7.28–7.32(m,2H),7.34–7.39(m,1H),7.43(s,1H),7.52(s,1H),7.77–7.83(m,1H)ppm.13C NMR(100MHz,CDCl3)δ=14.2,17.1,20.6,22.0,30.0,31.9,47.2,109.1,109.6,119.7,122.5,122.7,123.98,124.02,126.0,126.1,127.6,129.6,129.8,130.0,130.5,134.5,135.2,135.4,136.8,141.2,141.8,143.0,143.3,154.9,156.7ppm.HRMS(ESI+)calcd for C33H32N4[M+H]+485.2700,found 485.2696.
实施例11
目标产物结构式如下:
步骤同实施例1,以阿达帕林为原料。
产物为白色固体,产率为55%。
1H NMR(400MHz,CDCl3)δ=1.83(s,6H),2.13(s,3H),2.18–2.25(m,6H),2.54(s,3H),7.00(d,J=8.4Hz,1H),7.34(dd,J=8.4,1.6Hz,1H),7.54(dd,J=8.4,2.4Hz,1H),7.60–7.65(m,2H),7.71(dd,J=8.4,1.6Hz,1H),7.79–7.83(m,2H),7.96(s,1H)ppm.13C NMR(100MHz,CDCl3)δ=21.9,29.3,37.3,37.3,40.7,55.3,112.2,124.9,125.6,125.8,126.0,126.7,127.7,128.0,128.6,132.1,132.6,133.4,135.3,138.2,138.9,158.5ppm.
Claims (9)
1.一种制备甲基芳烃或甲基杂芳烃的方法,其特征在于:在惰性气体氛围下,将Ar–COOH、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应,得Ar–CH3;其中,所述Ar为芳基或杂芳基,所述芳基或杂芳基任选地被一个或更多个如下取代基取代:烷基、芳基、酰基、硝基、醛基、氰基、三氟甲基、甲氧基、磺酰基、磺胺基、酯基、胺基;
所述含钯催化剂选自二氯化钯、醋酸钯、三氟乙酸钯、二(乙酰丙酮)钯、三(二亚苄基丙酮)二钯中至少一种;所述膦配体选自双(2-二苯基膦苯基)醚、1,2-双(二苯基膦)乙烷、1,1’-双(二苯基膦)二茂铁、1,4-双(二苯基膦)丁烷、4,5-双(二苯基膦)-9,9’-二甲基氧杂蒽中至少一种;所述酸酐添加剂选自苯甲酸酐、乙酸酐、三氟乙酸酐、二碳酸二叔丁酯、三甲基乙酸酐中至少一种;
反应的温度为80~170℃,时间为6~36小时。
2.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法,其特征在于:所述芳基选自苯、萘、菲、蒽、芘,所述杂芳基选自喹啉、吡啶、苯并噻吩、苯并呋喃、吲哚、噻唑、咪唑、噁唑。
5.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法,其特征在于:所述溶剂选自THF、1,4-二氧六环、三氟甲苯、正己烷、甲苯中至少一种。
6.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法,其特征在于:所述含钯催化剂相对Ar–COOH的摩尔添加量为2.5%~10%;所述膦配体相对Ar–COOH的摩尔添加量为7.5%~30%;所述酸酐添加剂相对Ar–COOH的摩尔添加量为100%~300%。
7.根据权利要求5所述制备甲基芳烃或甲基杂芳烃的方法,其特征在于:所述含钯催化剂相对Ar–COOH的摩尔添加量为5%;所述膦配体相对Ar–COOH的摩尔添加量为15%;所述酸酐添加剂相对Ar–COOH的摩尔添加量为150%。
8.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法,其特征在于:Ar–COOH与三甲基环三氧硼烷的摩尔比为1:1~1:2。
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