CN102753513A - 制备芳基和杂芳基乙酸衍生物的方法 - Google Patents
制备芳基和杂芳基乙酸衍生物的方法 Download PDFInfo
- Publication number
- CN102753513A CN102753513A CN2011800095504A CN201180009550A CN102753513A CN 102753513 A CN102753513 A CN 102753513A CN 2011800095504 A CN2011800095504 A CN 2011800095504A CN 201180009550 A CN201180009550 A CN 201180009550A CN 102753513 A CN102753513 A CN 102753513A
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- China
- Prior art keywords
- propyl
- phenyl
- alkyl
- hydrogen
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 title abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- -1 sec.-propyl Chemical group 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- MWZAJEMJQMTNKM-UHFFFAOYSA-N bromomethylbenzene;n,n-diethylethanamine Chemical compound CCN(CC)CC.BrCC1=CC=CC=C1 MWZAJEMJQMTNKM-UHFFFAOYSA-N 0.000 claims description 9
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 8
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- IBGCXOFOCKCBNQ-UHFFFAOYSA-N nitro cyanate Chemical compound [O-][N+](=O)OC#N IBGCXOFOCKCBNQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- FVWCDFMLOYFXCE-UHFFFAOYSA-N naphthalen-1-ylphosphane Chemical compound C1=CC=C2C(P)=CC=CC2=C1 FVWCDFMLOYFXCE-UHFFFAOYSA-N 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- DTHDZKROQTVQNI-UHFFFAOYSA-N ClC.CCCCCCCCCCCCCN Chemical compound ClC.CCCCCCCCCCCCCN DTHDZKROQTVQNI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- VICYBMUVWHJEFT-UHFFFAOYSA-N dodecyltrimethylammonium ion Chemical compound CCCCCCCCCCCC[N+](C)(C)C VICYBMUVWHJEFT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- ANCWWFAROKLXRF-UHFFFAOYSA-M tetraethylazanium;iodate Chemical compound [O-]I(=O)=O.CC[N+](CC)(CC)CC ANCWWFAROKLXRF-UHFFFAOYSA-M 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract description 3
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 235000010338 boric acid Nutrition 0.000 description 12
- 239000004327 boric acid Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 5
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- MMEXIIGRXCODNK-UHFFFAOYSA-N 2-(2,6-dimethylphenyl)acetic acid Chemical compound CC1=CC=CC(C)=C1CC(O)=O MMEXIIGRXCODNK-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229960003424 phenylacetic acid Drugs 0.000 description 4
- 239000003279 phenylacetic acid Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 150000001502 aryl halides Chemical class 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- YCOZIPAWZNQLMR-UHFFFAOYSA-N heptane - octane Natural products CCCCCCCCCCCCCCC YCOZIPAWZNQLMR-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 3
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HTGQCLJTWPSFNL-UHFFFAOYSA-N (2-methylphenoxy)boronic acid Chemical compound CC1=CC=CC=C1OB(O)O HTGQCLJTWPSFNL-UHFFFAOYSA-N 0.000 description 1
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- ZLNFACCFYUFTLD-UHFFFAOYSA-N (4-ethoxycarbonylphenyl)boronic acid Chemical compound CCOC(=O)C1=CC=C(B(O)O)C=C1 ZLNFACCFYUFTLD-UHFFFAOYSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HIYXSFHDQCSEPT-UHFFFAOYSA-N 1-(1-phenylpiperidin-2-yl)ethanone Chemical class CC(=O)C1CCCCN1C1=CC=CC=C1 HIYXSFHDQCSEPT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 1
- GWJIPNKXIAJCPA-UHFFFAOYSA-N 2-bromo-1-piperidin-1-ylethanone Chemical class BrCC(=O)N1CCCCC1 GWJIPNKXIAJCPA-UHFFFAOYSA-N 0.000 description 1
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
本发明涉及一种制备式(III)α-芳基甲基羰基化合物的新方法,其特征在于式(I)的芳基和杂芳基乙酸及其衍生物与式(II)的α-卤代甲基羰基化合物在一种钯催化剂、一种膦配体、一种无机碱和一种相转移催化剂存在下反应,该反应任选地使用一种有机溶剂。
Description
本发明涉及一种制备芳基和杂芳基乙酸及其衍生物的方法,该方法通过在一种钯催化剂、一种碱和一种相转移催化剂存在下将芳基或杂芳基硼酸衍生物与α-卤代乙酸或其衍生物反应而进行。该方法能够制备多种官能化的芳基和杂芳基乙酸及其衍生物。另外其也可以用于制备其它α-芳基羰基化合物。
通常,苯基乙酸衍生物通过通常具有低基团容限(group tolerance)的多级合成而制备。制备可以例如由苯乙酮通过Willgerodt-Kindler反应(见例如H.E.Zaugg等人,J.Amer.Chem.Soc.70(1948)3224-8)而制备。然而该方法产生大量含硫废物。另外,可能出现高度恶臭的挥发性硫化合物。
另一种制备芳基乙酸的方法由苄基溴或苄基氯进行。例如***用于制备相应的腈,并且随后使其水解。所需的苄基溴或苄基氯可以例如通过相应的芳香族化合物的溴甲基化或氯甲基化而获得。然而,此处的一个不利之处为不能排除出现高度致癌的化合物(例如二(氯甲基)醚或二(溴甲基)醚)的情况,因此在工业中必须采取高水平的安全措施。此外,被取代的芳香族化合物的卤甲基化在许多情况下导致异构体混合物。
苄基卤在醇存在下的羰基化作用同样提供苯基乙酸酯。一些情况下甚至在升高的压力下,已经提及的苄基卤有限的可利用率和需要使用有毒CO气体,为该方法的另外的不利之处。
已经已知的另一方法为对α-氯苯乙酮进行缩酮化(ketalize)并且然后使该缩酮进行重排反应(C.Giordano等人,Angew.Chem.96(1984)413-9)。α-氯苯乙酮通过氯化苯乙酮或直接通过所述芳香族化合物与氯乙酰氯的Friedel-Crafts酰化作用而获得。这又产生了缺点:在被取代的芳香族化合物上的Friedel-Crafts酰化作用通常没有选择性地进行。
制备苯基乙酸的另一种已知的方法包括:在第一步重氮化一种相应的苯胺,第二步将所得的重氮化合物与亚乙烯基二氯反应,然后在第三步中将由此获得的三氯乙基或溴二氯乙基化合物与水或醇反应而得到芳基乙酸或其酯(见例如V.M.Naidan和A.V.Dombrovskii,ZhurnalObshchei Khimii34(1984)1469-73;EP-A-835243)。然而该反应通常仅在使用芳环上具有吸电子基团并且其中氨基没有空间封闭(block)的那些苯胺时才能得到好的产率。
同样已知的是溴苯与氯乙酸衍生物在化学计算量的银或铜存在下在180-200°C的反应。这些方法的不利之处在于,高温,这排除了在热敏化合物的情况下使用所述方法;低产率;和使用化学计算量的难以再处理的昂贵金属(expensive metal)。
芳基格利雅(Grignard)化合物与α-卤代乙酸衍生物的反应同样导致苯基乙酸衍生物。然而,一个不利之处在于由于使用难于处理的高反应性格利雅化合物而产生的官能团容限极端有限。
同样已知的是通过将芳基卤与丙二酸二烷基酯反应同时进行去烷氧基羰基化来制备芳基乙酸衍生物(Tetrahedron Lett.2004,45,5823-5)。然而,其具有的不利之处为,所需的碱是昂贵的碳酸铯。
作为所述方法的一个替代方案,还已记载了芳基卤与Reformatsky试剂、锡烯醇化物、铜烯醇化物和其它烯醇化物或乙烯酮缩二乙醇的交叉-偶联(见例如J.Am.Chem.Soc.1959,81,1627-1630;J.Organomet.Chem.1979,177,273-281;Synth.Comm.1987,17,1389-1402;Bull.Chem.Soc.Jpn.1985,58,3383-3384;J.Org.Chem.1993,58,7606-7607;J.Chem.Soc.Perkin 1 1993,2433-2440;J.Am.Chem.Soc.1975,97,2507-2517;J.Am.Chem.Soc.1977,99,4833-4835;J.Am.Chem.Soc.1999,121,1473-78;J.Org.Chem.1991,56,261-263,Heterocycles 1993,36,2509-2512,Tetrahedron Lett.1998,39,8807-8810。这类反应的综述可见于:Chem.Rev.2010,110,1082-1146和Angew.Chem.2010,122,686-718)。
然而,这些方法的应用性有限。例如,Reformatsky试剂和乙烯酮缩二乙醇难以制备和处理。出于毒物学原因使用锡化合物是不利的,并且使用化学计算量的铜在处理中产生相当大的费用。使用烯醇化物通常仅当在分子中没有另外的可烯醇化的基团存在时可行。因此例如对于该方法排除使用酮作为底物。一些电化学方法同样已知(Synthesis 1990,369-381;J.Org.Chem.1996,61,1748-1755),但是这些方法由于复杂的反应机制和低的时空产率而是不利的。
同样已知的是一种通过广泛可得、易于处理和稳定的芳基硼酸和溴乙酸乙酯之间的钯催化偶联反应而制备苯基乙酸衍生物的方法(L.J.Gooβen,Chem.Commun.2001,660-70;DE-A-10111262)。然而,到目前为止仍不可能使用该方法用于制备空间位阻要求高的苯基乙酸衍生物,例如2,6-二取代的苯基乙酸衍生物。Chem.Commun.2001,660-70确实陈述了空间位阻芳基硼酸在其中所述条件下同样可以有效率地转化。然而,实施例仅包括2-甲苯基硼酸作为一种空间位阻底物。没有描述更多空间限制的芳基硼酸,例如2,6-二芳基苯基硼酸。内部测试(见对比实施例1)证明,上述方法在该情况下仅得到不令人满意产率的芳基乙酸衍生物。
因此到目前为止已知的制备具有空间位阻要求高的取代的苯基乙酸衍生物的所有方法均具有缺陷和不足,其中一些具有相当多的缺陷和不足,这使其应用复杂化。一般而言由于苯基乙酸且特别是其中具有空间位阻要求高的取代的苯基乙酸为重要的前体,例如用于作物保护中活性成分的前体,因此需要一种技术上简单并且高效率的方法用于制备该化合物。
出人意料地,现已发现一种由芳基和杂芳基硼酸衍生物以及α-卤代乙酸及其衍生物制备芳基和杂芳基乙酸及其衍生物的方法,其特征在于反应在一种钯催化剂、一种膦、一种无机碱和一种相转移催化剂存在下进行。
加入相转移催化剂对反应的选择性具有积极影响这一发现是不能预见的,使该方法的发现特别地出人意料。
由于使用相转移催化剂,首次可以使选择性显著地向有利于所需产物的方向移动。更特别地是,抑制在质子脱硼烷基化作用(protodeborylation)下形成芳烃。仅形成一小部分不需要的副产物。
此外,加入相转移催化剂具有使极大转化率所需要的钯催化剂用量可显著降低的效果。这使该方法与现有技术已知的方法相比在经济上更可行得多。
本发明的方法不限于具有空间位阻要求高的取代的芳基硼酸。具有不同类型取代的芳基硼酸在本发明条件下同样可以以更高的产率转化。
依据本发明制备芳基和杂芳基羰基化合物的方法的特征在于式(I)的芳基或杂芳基硼酸与式(II)的α-卤代甲基羰基化合物在一种钯催化剂、一种膦配体、一种无机碱和一种相转移催化剂存在下、任选地使用一种有机溶剂进行反应,从而得到式(III)的α-芳基甲基羰基化合物
其中
R1为氢或C1-C8烷基,
R2为氢或C1-C8烷基,或
R1和R2与其所连接的原子一起为一个饱和或不饱和、取代或未取代的环,
Ar为基团
其中
R5、R6、R7、R8和R9相同或不同并且各自独立地为氢、卤素、任选地被卤素取代的C1-C6烷基、C1-C6烷氧基、苯基、–CO-C1-C3烷基、–COO-C1-C6烷基或–COO-C6-C10芳基,
Ar基团另外还可以为杂芳基,例如2-吡啶基、3-吡啶基、4-吡啶基、2-呋喃基、3-呋喃基、2-噻吩基或3-噻吩基,或
Ar基团也可以为1-萘基或2-萘基,
其中
Hal为卤素,
R3为羟基,各自任选地被取代的C1-C8烷基、C1-C8烷氧基、苯基、芳基、苯氧基或芳氧基,或NR4R4’,
其中R4和R4’相同或不同并且各自独立地为氢、C1-C4烷基或任选地被C1-C3烷基(其可以被氟或氯取代)、或被硝基、氰基或二C1-C3烷基氨基取代的苯基;或与其所连接的氮原子一起为一个饱和或不饱和、取代或未取代的环,
其中Ar和R3各自如上所定义。
本反应通过下面反应方程式阐明:
上文和下文提及的式中所示基团的优选取代基和范围在下文中阐明:
R1优选为氢或C1-C4烷基,
R2优选为氢或C1-C4烷基,或
R1和R2与其所连接的原子一起优选为任选地被C1-C4烷基或芳基(特别是苯基)取代的C2-C3烷二基,
R3优选为羟基、任选地被氟取代的C1-C4烷基、C1-C4烷氧基,各自任选地被取代的苯基、苯氧基,或NR4R4’,
其中R4和R4’优选相同或不同并且各自独立地为氢、甲基、乙基、异丙基、正丙基或任选地被甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、硝基、氰基、N(甲基)2、N(乙基)2、N(正丙基)2、N(异丙基)2取代的苯基;或与其所连接的氮原子一起为饱和或不饱和、取代或未取代的5或6元环,
Ar优选为1-萘基或2-萘基或基团
其中
R5、R6、R7、R8和R9优选相同或不同并且各自独立地为氢、氟、氯、任选地被氟取代的C1-C4烷基、C1-C4烷氧基、苯基、–CO-C1-C3烷基、–COO-C1-C4烷基或–COO-C6-C8芳基、
Hal优选为氟、氯、溴或碘。
R1更优选为氢、甲基、乙基、异丙基或正丙基,
R2更优选为氢、甲基、乙基、异丙基或正丙基,或
R1和R2与其所连接的原子一起更优选为任选地被一甲基至四甲基取代的C2-烷二基、任选地被一甲基至六甲基取代的C3-烷二基(强调的是–CH2C(CH3)2CH2-、-C(CH3)2C(CH3)2-),
R3更优选为甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、甲氧基、乙氧基、异丙氧基、正丙氧基或叔丁氧基,各自任选地被取代的苯基,或NR4R4’,
其中R4和R4’更优选相同或不同并且各自独立地为氢、甲基、乙基、异丙基、正丙基或与其所连接的氮原子一起为一个饱和的、未取代的5或6元环,
Ar更优选为1-萘基或基团
其中
R5、R6、R7、R8和R9更优选相同或不同并且各自独立地为氢、氟、氯、甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、甲氧基、乙氧基、苯基、–CO-甲基、–CO-乙基、–COO-甲基、–COO-乙基或–COO-苯基,
Hal更优选为氯、溴或碘。
R1更优选为氢,
R2更优选为氢,
R3最优选为甲氧基、乙氧基、叔丁氧基、苯基或NR4R4’,
其中R4和R4’与其所连接的氮原子一起为一个饱和的未取代的6元环,
Ar最优选为1-萘基、苯基、2,6-二甲基苯基、2,4,6-三甲基苯基、4-乙酰基苯基、4-氯代-2,6-二甲基苯基、2,6-二乙基-4-甲基苯基、4-甲氧基苯基、4-乙氧基羰基苯基,
Hal最优选为溴。
上面给出的或在优选范围内给出的宽泛的基团定义和说明可以相互结合,即包括具体范围和优选范围之间的结合。其相应地适用于最终产物和中间体。
式(I)的硼酸原则上已知或可以通过已知的方法制备,例如由相应的溴代芳香族化合物、镁金属和硼酸三甲酯制备。
依据现有技术硼酸任选地也可以通过将相应的芳基卤或杂芳基卤与一种二硼化合物或与一种硼烷在一种钯催化剂存在下反应而原位(insitu)获得。
式(II)的化合物原则上已知或可以通过已知的方法制备。
本发明方法中使用的碱为无机碱,例如碱金属或碱土金属氢氧化物、碳酸盐、碳酸氢盐、氧化物、磷酸盐、磷酸氢盐、氟化物或氢氟化物。优选为使用碱金属和碱土金属磷酸盐、碳酸盐或氟化物,并且特别优选为使用氟化钾、碳酸钾和磷酸钾。强调的是使用氟化钾。
在本发明的方法中,使用1至10当量的具体碱。优选地,使用2-7当量的碱。
本发明方法中使用的钯催化剂为钯(II)盐,例如氯化钯、溴化钯、碘化钯、乙酸钯、乙酰丙酮酸钯,其任选地可通过另外的配体(例如烷基腈)或Pd(0)物质进行稳定,所述Pd(0)物质例如负载于活性炭上的钯、Pd(PPh3)4、二(二亚苄基丙酮)钯或三(二亚苄基丙酮)二钯。优选为二(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯、氯化钯、溴化钯和乙酸钯;强调是二(二亚苄基丙酮)钯。
本发明方法中所使用的钯催化剂的量为0.001至5mol%,基于所用的芳基硼酸计。优选地,使用0.005至3mol%;特别优选使用0.01至1mol%。
本发明方法中所使用的膦配体为配体PR10R11R12,其中基团R10、R11和R12各自为氢、直链和支链C1-C8烷基、乙烯基、芳基或选自吡啶、嘧啶、吡咯、噻吩或呋喃的杂芳基,而其又可以被选自以下的另外的取代基所取代:直链和支链C1-C8烷基或C6-C10芳基、直链和支链C1-C8烷氧基或C1-C10芳氧基、卤代直链和支链C1-C8烷基或卤化C6-C10芳基、直链和支链C1-C8烷基或C6-C10芳氧基羰基、直链和支链C1–C8烷基氨基、直链和支链C1–C8二烷基氨基、C1–C8芳基氨基、C1–C8二芳基氨基、甲酰基、羟基、羧基、氰基和卤素(例如F、Cl、Br和I)。
优选的膦配体为三苯基膦、三(1-萘基)膦和三(邻甲苯基)膦。强调的是三(1-萘基)膦和三(邻甲苯基)膦。
或者,也可以使用所限定的钯络合物,其由上面提及的配体经过一个或多个操作步骤而预先获得。
在本发明方法中,使用1-20mol当量的膦,基于所用钯的量计。优选使用1-4mol当量。
在本发明方法中,使用选自下面的一种相转移催化剂:季铵盐、季鏻盐和金属盐,其转而又由冠醚或穴状配体溶解。
该相转移催化剂优选具有通式(IV)
基团R13、R14、R15和R16相同或不同并且各自独立地为C1–C28烷基、任选地支链C1–C28烷基、C6-C10芳基或苯甲基。
X基团为卤素、硫酸氢根、硫酸根、磷酸二氢根、磷酸氢根、磷酸根或乙酸根。
X优选为溴、氯、氟、硫酸氢根、硫酸根、磷酸根和乙酸根。
该相转移催化剂的实例包括氟化四丁基铵、氯化四丁基铵、溴化四丁基铵、碘化四丁基铵、乙酸四丁基铵、碘化四乙基铵、溴化苯甲基三乙基铵、溴化十二烷基三甲基铵和氯化甲基十三烷基铵(Aliquat 336)。强调的是氟化四丁基铵、乙酸四丁基铵和溴化苯甲基三乙基铵。
本发明方法中相转移催化剂的量为1至50mol%,基于芳基硼酸计。优选为5至20mol%的量。
本发明的方法在-20℃至200℃温度下进行,优选0℃至150℃并且更优选为20℃至120℃。
本发明的方法可在一种溶剂存在下或在本体中进行。优选为在一种溶剂存在下进行。优选的溶剂为饱和脂族烃、脂环烃、芳香烃、醇类、酰胺类、亚砜类、磺酸盐类、腈类、酯类或醚类。
例如,所用的溶剂可以为戊烷、己烷、庚烷、辛烷、环己烷、甲苯、二甲苯、乙苯、均三甲苯、二氧杂环己烷、四氢呋喃、二丁醚、甲基叔丁基醚、二异丙基醚、二甘醇二甲醚、甲醇、乙醇、丙醇、异丙醇、乙酸甲酯、乙酸乙酯、乙酸叔丁酯、二甲基甲酰胺、二乙基甲酰胺、N-甲基吡咯烷酮、二甲基乙酰胺、二甲基亚砜、环丁砜、乙腈、丙腈或水。
特别优选为使用芳香烃、酰胺类、酯类和醚类。极特别优选为使用醚类。
本发明的方法通常在标准压力下进行,但是也可以在降低或提高的压力下进行。
为分离依据本发明制备的芳基和杂芳基乙酸及其衍生物,反应终止后,反应混合物优选通过蒸馏和/或通过萃取进行后处理。优选通过萃取并随后蒸馏对反应混合物进行后处理。
本发明的方法通过下面实施例进行阐明,而不受其限制。
实施例1:2,6-二甲基苯基乙酸乙酯
最初在一个装配有磁力搅拌器、回流冷凝器和滴液漏斗的25ml三颈烧瓶中加入20ml经分子筛干燥的四氢呋喃(THF)。将THF加热至50℃并且通氩气数分钟,然后重新冷却至室温。仍然在氩气下,加入下面物质:17.2mg[0.03mmol=0.3mol%]的二(二亚苄基丙酮)钯、27.4mg的P(邻甲苯基)3(三邻甲苯基膦)[0.09mmol]、2.91g的氟化钾(在140℃下经P2O5干燥)、272mg[1mmol=10mol%]的溴化苯甲基三乙基铵、1.5g[10mmol]的2,6-二甲基苯基硼酸和2.56g[15mmol]的溴乙酸乙酯。将该混合物在温和氩气流中在回流下搅拌24小时。然后将其通过少量硅藻土过滤,滤饼每次用20ml乙酸乙酯洗涤,洗涤三次。将合并的滤液用20ml的1N盐酸振荡萃取。将水相每次用20ml乙酸乙酯反萃取,进行两次。然后将合并的有机相用20ml饱和NaCl水溶液洗涤,干燥并浓缩。这样得到2.16g的一种油,依据GC-MS,该油除含有8.9面积%的间二甲苯外,还含有72.9面积%的2,6-二甲基苯基乙酸乙酯。这对应于理论值的81.9%的产率。
对比实施例1:2,6-二甲基苯基乙酸乙酯
最初在一个装配有磁力搅拌器、回流冷凝器和滴液漏斗的25ml三颈烧瓶中加入20ml经分子筛干燥的四氢呋喃(THF)和0.36ml的水。将该混合物加热至50℃并且通氩气数分钟,然后重新冷却至室温。仍然在氩气下,加入下面物质:17.2mg[0.03mmol=0.3mol%]的二(二亚苄基丙酮)钯、27.4mg的P(邻甲苯基)3[0.09mmol]、2.91g的氟化钾(在140℃下经P2O5干燥)、1.5g[10mmol]的2,6-二甲基苯基硼酸和2.56g[15mmol]的溴乙酸乙酯。将该混合物在温和氩气流中在回流下搅拌24小时。然后将其通过少量硅藻土过滤并且滤饼每次用20ml乙酸乙酯洗涤,洗涤三次。将合并的滤液用20ml的1N盐酸振荡萃取。将水相每次用20ml乙酸乙酯反萃取,进行两次。然后将合并的有机相用20ml饱和NaCl水溶液洗涤,干燥并浓缩。这样得到1.59g的一种油,依据GC-MS,该油除含有10.7面积%的间二甲苯外,还含有56.6面积%的2,6-二甲基苯基乙酸乙酯。这对应于理论值的46.8%的产率。
实施例2至10
一般性实验说明
在大气氧下将硼酸(1.00mmol)、Pd(dba)2(二(二亚苄基丙酮)钯)(1.73mg,3.00μmol)、三邻甲苯基膦(2.74mg,9.00μmol)、溴化苯甲基三乙基铵(27.8mg,0.10mmol)和氟化钾(174mg,3.00mmol)加入至20ml管瓶中。密封该容器,抽真空三次并再充入氮气。在搅拌期间加入溴乙酸乙酯(167mg,166μl,1.50mmol)和2ml的THF(干燥,用氩气脱气)。将该反应混合物在60℃下搅拌24小时。反应时间期满后,冷却混合物,加入50μl的正十四烷,取0.25ml样品并在3ml乙酸乙酯和2ml水中洗,并且提取该0.25ml样品,用含有硅藻土/碱性氧化铝的吸量管过滤,然后通过GC分析。
后处理:将反应溶液通过一种硅藻土/碱性氧化铝(1:2)结合物过滤。滤饼用乙酸乙酯洗涤。浓缩滤液并通过柱色谱法(5:1,己烷/乙酸乙酯,硅胶)纯化。得到产品。
实施例2:2,4,6-三甲基苯基乙酸乙酯
依据一般性实验方法由2,4,6-三甲基苯基硼酸(164mg,1.00mmol)制备2,4,6-三甲基苯基乙酸乙酯。通过柱色谱法(己烷/乙酸乙酯,5:1,)后处理后,以理论值的62%的产率得到2,4,6-三甲基苯基乙酸乙酯,其为无色液体。1H NMR(200MHz,CDCl3):δ=6.89(s,2H),4.10-4.25(m,2H),3.67(s,2H),2.27-2.37(m,9H),1.27(t,J=7.1Hz,3H)ppm;13C NMR(50MHz,CDCl3):δ=171.9,137.4,136.8,129.3,129.2,61.1,35.6,21.3,20.6,14.7ppm;MS(70eV),m/z(%):206(23)[M+],160,(7),133(100),105(10)91(11);IR(NaCl):υ=2978(m),2867(w),1732(s),1157(m),1031(m)cm-1。
实施例3:4-乙酰基苯基乙酸乙酯
依据一般性实验方法由4-乙酰基苯基硼酸(164mg,1.00mmol)制备4-乙酰基苯基乙酸乙酯。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论值的60%的产率得到4-乙酰基苯基乙酸乙酯,其为无色固体。1H NMR(400MHz,CDCl3):δ=7.90(d,J=8.2Hz,2H),7.37(d,J=8.5Hz,2H),4.11-4.17(m,2H),3.66(s,2H),2.58(s,3H),1.20-1.27(m,3H)ppm;13C NMR(151MHz,CDCl3):δ=197.7,170.8,139.5,136.0,129.6,128.6,61.1,41.3,26.6,14.2ppm;MS(70eV),m/z(%):192(100),164(16),134(14),105(19),89(11);IR(KBr):υ=2981(w),1735(s),1682(m),1274(m),1178(m)cm-1;元素分析(理论值):C=69.89,H=6.84,(实验值):C=69.95,H=6.99。熔点:55-56°C。
实施例4:4-氯-2,6-二甲基苯基乙酸乙酯
依据一般性实验方法由4-氯-2,6-二甲基苯基硼酸(186mg,1.00mmol)制备4-氯-2,6-二甲基苯基乙酸乙酯。这包括使用290mg[5mmol]的KF和418mg[2.5mmol]溴乙酸乙酯。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论值的68%的产率得到4-氯-2,6-二甲基苯基乙酸乙酯,其为无色液体。1H NMR(400MHz,CDCl3):δ=7.02(s,2H),4.13(q,J=07.Hz,2H),3.62(s,2H),2.29(s,6H),1.23(t,J=7.2HZ,3H)ppm;13C NMR(101MHz,CDCl3):δ=170.8,139.0,132.2,131.6,130.3,127.9,113.6,60.8,35.0,20.1,14.2ppm;MS(70eV),m/z(%):226(22)[M+],180(9),153(100),115(17),91(11);IR(NaCl):υ=2980(m),1733(s),1328(w),1155(m),1030(m)cm-1;元素分析:(理论值):C=63.58,H=6.67,(实验值):C=63.30,H=6.78。
实施例5:2,6-二乙基-4-甲基苯基乙酸乙酯
依据一般性实验方法由2,6-二乙基-4-甲基苯基硼酸(186mg,1.00mmol)制备2,6-二乙基-4-甲基苯基乙酸乙酯。这包括使用5.75mg[0.01mmol]的Pd(dba)2和9.1mg[0.03mmol]的P(邻甲苯基)3。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论酯的54%的产率得到2,6-二乙基-4-甲基苯基乙酸乙酯,其为无色液体。1H NMR(400MHz,CDCl3):δ=6.91(s,2H),4.16(q,J=7.2Hz,2H),3.71(s,2H),2.61-2.69(m,4H),2.32(s,3H),1.19-1.28(m,9H)ppm;13C NMR(101MHz,CDCl3):δ=171.9,143.0,136.7,127.2,127.1,60.6,34.0,26.4,21.1,15.1,14.2ppm;MS(70eV),m/z(%):234(37)[M+],161(100),147(33),133(40),119(13);IR(NaCl):υ=2966(s),1739(s),1458(w),1156(m),1032(m)cm-1;元素分析:(理论值):C=76.88,H=9.46,(实验值):C=75.85,H=9.38。
实施例6:1-萘乙酸乙酯
依据一般性实验方法由1-萘硼酸(172mg,1.00mmol)制备1-萘乙酸乙酯。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论值的77%的产率得到1-萘乙酸乙酯,其为无色液体。1H NMR(600MHz,CDCl3):δ=8.04(d,J=8.3Hz,1H),7.89(d,J=8.1Hz,1H),7.80-7.84(m,1H),7.55-7.58(m,1H),7.50-7.54(m,1H),7.43-7.47(m,2H),4.16-4.20(m,2H),4.09(s,2H),1.23-1.27(m,3H)ppm;13C NMR(151MHz,CDCl3):δ=171.7,133.9,132.2,130.8,128.8,128.1,128.0,126.4,125.8,125.6,123.9,61.0,39.4,14.3ppm;MS(70eV),m/z(%):214(100)[M+],141(34),115(45),89(9),63(6);IR(NaCl):υ=3047(w),2981(m),1733(s),1173(m),1029(m)cm-1,元素分析:(理论值):C=78.48,H=6.59,(实验值):C=78.35,H=6.86。
实施例7:4-甲氧基苯基乙酸乙酯
依据一般性实验方法由4-甲氧基苯基硼酸(152mg,1.00mmol)制备4-甲氧基苯基乙酸乙酯。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论值的77%的产率得到4-甲氧基苯基乙酸乙酯,其为无色液体。1H NMR(200MHz,CDCl3):δ=7.25(d,J=8.5Hz,2H),6.91(d,J=8.7Hz,2H),4.13-4.26(m,2H),3.82(s,3H),3.59(s,2H),1.24-1.26(m,3H)ppm;13C NMR(50MHz,CDCl3):δ=172.3,159.1,130.7,126.7,114.4,61.1,55.6,40.9,14.6ppm;MS(70eV),m/z(%):194(24)[M+],121(100),91(8),77(10),51(4);IR(NaCl):υ=2981(m),2836(w),1732(s),1513(s),1247(m),1032(m)cm-1;元素分析:(理论值):C=68.02,H=7.27,(实验值):C=67.91,H=7.18。
实施例8:4-乙氧基羰基苯基乙酸乙酯
依据一般性实验方法由4-乙氧基羰基苯基硼酸(194mg,1.00mmol)制备1,4-苯基二乙酸-1,4-二乙基酯。通过柱色谱法(己烷/乙酸乙酯,5:1)后处理后,以理论值的71%的产率得到1,4-苯基二乙酸-1,4-二乙基酯,其为黄色液体。1H NMR(600MHz,CDCl3):δ=8.12(d,J=8.6Hz,1H),7.99(d,J=8.3Hz,1H),7.67(d,J=8.3Hz,1H),7.34(d,J=8.1Hz,1H),4.38-4.42(m,1H),4.34-4.37(m,1H),4.12-4.16(m,1H),3.65(s,1H),1.36-1.42(m,4H),1.22-1.26(m,2H)ppm;13C NMR(151MHz,CDCl3):δ=170.9,166.4,139.2,130.2,129.8,129.4,129.3,127.2,61.1,61.0,41.4,14.4,14.2ppm;MS(70eV),m/z(%):237(6)[M+],191(39),163(100),135(39),118(13);IR(NaCl):υ=2982(m),2938(w),1735(s),1718(s)1277(s)cm-1;元素分析:(理论值):C=66.09,H=6.83,(实验值):C=65.98,H=7.05。
实施例9:2,6-二甲基苯基乙酸乙酯
依据一般性方法使用0.1mmol氟化四丁基铵代替溴化苯甲基三乙基铵制备2,6-二甲基苯基乙酸乙酯,产率为理论值的63%。
实施例10:2,6-二甲基苯基乙酸乙酯
依据一般性方法使用0.1mmol乙酸四丁基铵代替溴化苯甲基三乙基铵制备2,6-二甲基苯基乙酸乙酯,产率为理论值的66%。
实施例11:ω-(2,6-二甲基苯基)苯乙酮
在大气氧下将2,6-二甲基苯基硼酸(151mg,1.01mmol)、ω-溴代苯乙酮(299mg,1.50mmol)、Pd(dba)2(5.75mg,10.0μmol)、三邻甲苯基膦(10.0mg,32.9μmol)、溴化苯甲基三乙基铵(27.2mg,0.10mmol)和氟化钾(323mg,5.56mmol)加入至20ml管瓶中。密封该容器,抽真空三次并再充入氮气。在搅拌期间加入2ml的THF(干燥,用氩气脱气)。将反应混合物在60℃下搅拌24小时。反应时间终了后,冷却混合物,加入50μl的正十四烷,取0.25ml样品并在3ml乙酸乙酯和2ml水中洗涤,并且提取0.25ml该样品,用含有硅藻土/碱性氧化铝的吸量管过滤,然后通过GC分析。
后处理:将反应溶液通过一种硅藻土/碱性氧化铝(1:2)结合物过滤。滤饼用乙酸乙酯洗涤。浓缩滤液并通过柱色谱法(5:1,己烷/乙酸乙酯,硅胶)纯化。这样得到:ω-(2,6-二甲基苯基)苯乙酮(106mg,0.473mmol,理论值的47%)。
1H NMR(400MHz,CDCl3):δ=8.16(d,J=7.2Hz,2H),7.66(d,J=7.4Hz,1H),7.51-7.61(m,2H),7.12-7.21(m,3H),4.45(s,2H),2.30(s,6H)ppm;13C NMR(101MHz,CDCl3):δ=196.9,137.4,137.0,133.1,132.5,128.7,128.1,128.0,126.9,39.7ppm;MS(70eV),m/z(%):224(11)[M+],119(9),106(8),105(100),91(9),77(33),51(11);元素分析:(理论值):C=85.68,H=7.19,(实验值):C=85.39,H=7.22;熔点:113-114°C。
实施例12:N-(苯基乙酰基)哌啶
在大气氧下将苯硼酸(122mg,1.00mmol)、Pd(dba)2(1.73mg,3.0μmol)、三-1-萘基膦(3.71mg,9.00μmol)、溴化苯甲基三乙基铵(27.2mg,0.10mmol)和氟化钾(290mg,5.00mmol)加入至20ml管瓶中。密封该容器,抽真空三次并再充入氮气。在搅拌期间加入N-(溴代乙酰基)哌啶(309mg,1.50mmol)和2ml的THF(干燥,用氩气脱气)。将反应混合物在60℃下搅拌24小时。反应时间终了后,冷却混合物,加入50μl的正十四烷,取0.25ml样品并在3ml乙酸乙酯和2ml水中洗涤,并且提取0.25ml该样品,用含有硅藻土/碱性氧化铝的吸量管过滤,然后通过GC分析。
后处理:将反应溶液通过一种硅藻土/碱性氧化铝(1:2)结合物过滤。滤饼用乙酸乙酯洗涤。浓缩滤液并通过柱色谱法(1:2,己烷/乙酸乙酯,硅胶)纯化。这样得到:N-苯基乙酰基哌啶(169mg,0.714mmol,理论值的71%)。
1H NMR(600MHz,CDCl3):δ=7.29(t,J=7.5Hz,2H),7.19-7.24(m,2H),3.71(s,2H),3.52-3.56(m,2H),3.33-3.37(m,2H),1.60-1.65(m,1H),1.52-1.57(m,2H),1.47-1.52(m,2H),1.30-1.34(m,2H)ppm;13C NMR(151MHz,CDCl3):δ=169.3,135.5,128.7,126.6,48.0,47.3,43.3,42.9,41.2,31.0,26.2,25.5,25.4,24.3ppm;MS(70eV),m/z(%):203(44)[M+],112(100),91(41),84(14),69(57),65(18),41(29)。
Claims (8)
1.制备式(III)化合物的方法
其中
Ar为基团
Ar为一个杂芳基,例如2-吡啶基、3-吡啶基、4-吡啶基、2-呋喃基、3-呋喃基、2-噻吩基或3-噻吩基,或
A为1-萘基或2-萘基,
其中R5、R6、R7、R8和R9相同或不同并且各自独立地为氢、卤素、任选地卤素取代的C1-C6烷基、C1-C6烷氧基、苯基、–CO-C1-C3烷基、–COO-C1-C6烷基或–COO-C6-C10芳基,
R3为羟基,各自任选地被取代的C1-C8烷基、C1-C8烷氧基、苯基、芳基、苯氧基或芳氧基,或NR4R4’,
其中R4和R4’相同或不同并且各自独立地为氢、C1-C4烷基或任选地被C1-C3烷基或被硝基、氰基或二C1-C3烷基氨基取代的苯基,所述C1-C3烷基可以被氟或氯取代;或与其所连接的氮原子一起为一个饱和或不饱和、取代或未取代的环,
其特征在于
式(I)的化合物与式(II)的化合物在一种钯催化剂、一种膦配体、一种无机碱和一种相转移催化剂存在下、任选地使用一种有机溶剂进行反应
其中
R1为氢或C1-C8烷基,
R2为氢或C1-C8烷基,或
R1和R2与其所连接的原子一起为一个饱和或不饱和、取代或未取代的环,
并且Ar如上所定义
其中
Hal为卤素,
并且R3如上所定义。
2.权利要求1的制备式(III)化合物的方法,其特征在于
R1为氢或C1-C4烷基,
R2为氢或C1-C4烷基,或
R1和R2与其所连接的原子一起为任选地被C1-C4烷基或芳基取代的C2-C3烷二基,
R3为羟基、任选地被氟取代的C1-C4烷基、C1-C4氧基,各自任选地被取代的苯基、苯氧基,或NR4R4’,
其中R4和R4’相同或不同并且各自独立地为氢、甲基、乙基、异丙基、正丙基或任选地被甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、硝基、氰基、N(甲基)2、N(乙基)2、N(正丙基)2、N(异丙基)2取代的苯基;或与其所连接的氮原子一起,为饱和或不饱和、取代或未取代的5或6元环,
Ar为1-萘基或2-萘基或基团
其中
R5、R6、R7、R8和R9相同或不同并且各自独立地为氢、氟、氯、任选地氟取代的C1-C4烷基、C1-C4烷氧基、苯基、–CO-C1-C3烷基、–COO-C1-C4烷基或–COO-C6-C8芳基,
Hal为氟、氯、溴或碘。
3.权利要求1的制备式(III)化合物的方法,其特征在于
R1为氢、甲基、乙基、异丙基或正丙基,
R2为氢、甲基、乙基、异丙基或正丙基,或
R1和R2与其所连接的原子一起为任选地被一甲基至四甲基取代的C2-烷二基、任选地被一甲基至六甲基取代的C3-烷二基,
R3为甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、甲氧基、乙氧基、异丙氧基、正丙氧基或叔丁氧基,各自任选地被取代的苯基,或NR4R4’,
其中R4和R4’相同或不同并且各自独立地为氢、甲基、乙基、异丙基、正丙基或与其所连接的氮原子一起为一个饱和的、未取代的5或6元环,
Ar为1-萘基或基团
其中
R5、R6、R7、R8和R9相同或不同并且各自独立地为氢、氟、氯、甲基、乙基、异丙基、正丙基、CF3、C2F5、C3F7、甲氧基、乙氧基、苯基、–CO-甲基、–CO-乙基、–COO-甲基、–COO-乙基或–COO-苯基,
Hal为氯、溴或碘。
4.权利要求1的制备式(III)化合物的方法,其特征在于
R1为氢,
R2为氢,
R3为甲氧基、乙氧基、叔丁氧基、苯基或NR4R4’,
其中R4和R4’与其所连接的氮原子一起为一个饱和的、未取代的6元环,
Ar为1-萘基、苯基、2,6-二甲基苯基、2,4,6-三甲基苯基、4-乙酰基苯基、4-氯-2,6-二甲基苯基、2,6-二乙基-4-甲基苯基、4-甲氧基苯基、4-乙氧基羰基苯基,
Hal为溴。
5.权利要求1的制备式(III)化合物的方法,其特征在于所使用的钯催化剂为二(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯、氯化钯、溴化钯或乙酸钯。
6.权利要求1的制备式(III)化合物的方法,其特征在于所使用的膦配体为三苯基膦、三(1-萘基)膦或三(邻甲苯基)膦。
7.权利要求1的制备式(III)化合物的方法,其特征在于所使用的碱为氟化钾、碳酸钾或磷酸钾。
8.权利要求1的制备式(III)化合物的方法,其特征在于所使用的相转移催化剂为氟化四丁基铵、氯化四丁基铵、溴化四丁基铵、碘化四丁基铵、乙酸四丁基铵、碘化四乙基铵、溴化苯甲基三乙基铵、溴化十二烷基三甲基铵或氯化甲基十三烷基铵。
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E. PAETZOLD,ET AL.: "Efficient two-phase Suzuki reaction catalyzed by palladium complexes with water-soluble phosphine ligands and detergents as phase transfer reagents", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》 * |
LUKAS J. GOOSSEN: "Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acids", 《CHEMICAL COMMUNICATION》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113121341A (zh) * | 2019-12-31 | 2021-07-16 | 江苏中旗科技股份有限公司 | 一种合成2,6-二乙基-4-甲基苯乙酸酯的方法 |
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US8507688B2 (en) | 2013-08-13 |
WO2011089072A1 (de) | 2011-07-28 |
IN2012DN06383A (zh) | 2015-10-02 |
KR101773070B1 (ko) | 2017-09-12 |
JP5899119B2 (ja) | 2016-04-06 |
EP2526081A1 (de) | 2012-11-28 |
DK2526081T3 (en) | 2015-10-05 |
ES2546487T3 (es) | 2015-09-24 |
KR20120116491A (ko) | 2012-10-22 |
JP2013517255A (ja) | 2013-05-16 |
EP2526081B1 (de) | 2015-07-01 |
IL220787A (en) | 2015-05-31 |
CN102753513B (zh) | 2015-03-18 |
US20110184180A1 (en) | 2011-07-28 |
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