CN104672221B - A kind of synthetic method of fluoro benzheterocycle Heteroaryl ring structures - Google Patents
A kind of synthetic method of fluoro benzheterocycle Heteroaryl ring structures Download PDFInfo
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- CN104672221B CN104672221B CN201310630194.9A CN201310630194A CN104672221B CN 104672221 B CN104672221 B CN 104672221B CN 201310630194 A CN201310630194 A CN 201310630194A CN 104672221 B CN104672221 B CN 104672221B
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- alkyl
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- 125000001153 fluoro group Chemical group F* 0.000 title claims abstract description 9
- 238000010189 synthetic method Methods 0.000 title abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 38
- 150000002940 palladium Chemical class 0.000 claims abstract description 19
- 239000007800 oxidant agent Substances 0.000 claims abstract description 15
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000758 substrate Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 128
- 150000001875 compounds Chemical class 0.000 claims description 119
- 150000003254 radicals Chemical class 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- -1 phenyl Chemical group 0.000 claims description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 32
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 25
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 229930192474 thiophene Natural products 0.000 claims description 7
- 150000003577 thiophenes Chemical class 0.000 claims description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 6
- 150000001879 copper Chemical class 0.000 claims description 6
- 150000002240 furans Chemical class 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical group [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical group CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 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 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000004057 1,4-benzoquinones Chemical class 0.000 claims description 3
- 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 3
- 125000000739 C2-C30 alkenyl group Chemical group 0.000 claims description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000005751 Copper oxide Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229940116318 copper carbonate Drugs 0.000 claims description 3
- 229910000431 copper oxide Inorganic materials 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229950010765 pivalate Drugs 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940071536 silver acetate Drugs 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- 229940096017 silver fluoride Drugs 0.000 claims description 3
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 229910001923 silver oxide Inorganic materials 0.000 claims description 3
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 3
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052733 gallium Inorganic materials 0.000 claims description 2
- 229910052714 tellurium Inorganic materials 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 23
- 239000011737 fluorine Substances 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000004065 semiconductor Substances 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 129
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- 238000004293 19F NMR spectroscopy Methods 0.000 description 29
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 23
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000006073 displacement reaction Methods 0.000 description 5
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- 0 *c(c1n[n](*)nc1cc1F)c1I Chemical compound *c(c1n[n](*)nc1cc1F)c1I 0.000 description 3
- 229940126639 Compound 33 Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910004373 HOAc Inorganic materials 0.000 description 3
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-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 2
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of synthetic method of fluoro benzheterocycle Heteroaryl ring structures, specifically, benzheterocycle and its derivative and heteroaryl cyclics that methods described is substituted by simple fluorine, under the catalysis of palladium salt, oxidant is served as with silver salt, the method for obtaining the benzheterocycle heteroaryl cyclics of various fluorine substitutions in high yield.The benzheterocycle and heteroaryl cyclics that this method is substituted using simple fluorine are raw material, have the advantages that catalyst amount is few, and wide application range of substrates is easy to operate, and reaction efficiency is high.The benzheterocycle hetero-aromatic ring building block of the fluorine substitution of gained suffers from being widely applied in terms of organic semiconductor, photoelectric material and solar cell.
Description
Technical Field
The invention belongs to the field of organic synthesis. In particular, the invention relates to a synthetic method of a fluorobenzene heterocycle-heteroaromatic ring.
Background
Fluorobenzene heterocyclic-heteroaromatic rings play an important role in organic electronic devices (such as organic luminescent materials, photoelectric materials, field effect semiconductors, organic solar cells and the like). However, conventional methods for synthesizing fluorobenzene heterocycle-heteroaromatic rings are generally prepared from preactivated aromatic metal reagents (such as arylboron compounds, aryltin compounds, etc.) and halogenated fluorobenzene heterocycles (for example, (a) adv. mater.2012,24,3646-3649, (b) j. am. chem. soc.,2013,135(5), pp 1806-1815, (c) j. am. chem. soc.,2011,133(12), pp 4625-4631).
Therefore, the search for a safer and more convenient preparation method of the fluorobenzene heterocycle-heteroaromatic ring has significant meaning.
Disclosure of Invention
The invention aims to provide a safe and simple preparation method of fluorobenzene heterocycle-heteroaromatic ring and derivatives thereof.
In a first aspect, the present invention provides a process for the preparation of a compound of formula C, comprising the steps of:
reacting a compound of formula A with a compound of formula B in an inert solvent in the presence of an oxidant using a palladium salt as a catalyst to form a compound of formula C;
in the above-mentioned formulas, the first and second substrates,
R1、R2、R'1、R'2、R'3each independently of the other being H, cyano, halogen, C1-30Alkyl, halogenated C1-30Alkyl radical, C2-30Alkenyl, halogenated C2-30Alkenyl radical, C2-30Alkynyl, C substituted by halogen or phenyl2-30Alkynyl, C1-30Alkoxy, halogenated C1-30Alkoxy, -CONR6R7、-COOC1-30Alkyl radical, C1-30Alkyl-carbonyl, formyl, thiophene-substituted pyrrolopyrroledione groups, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C = C-COOC1-30An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-30Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-20Alkyl radical, C1-20Alkyl-carbonyl or formyl; or,
R1and R2、R'1And R'2Or R'2And R'3Together with the adjacent rings:
(a) a benzoheterocyclic group, or
(b) By one or more R4Substituted benzoheterocyclyl, wherein R4Selected from: cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, -CONR6R7、-COOC1-20Alkyl radical, C1-20Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C = C-COOC1-20Alkyl, wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl;
x is S, O, or NR5Y is S, O, Se, Te, Ga or NR5(ii) a Wherein R is5Is selected from: H. cyano radicals, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, haloC of (A)2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, -COOC1-20Alkyl radical, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C = C-COOC1-10Alkyl, substituted or unsubstituted benzyl; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl;
R6、R7each independently of the other being H, cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, -COOC1-20Alkyl radical, C1-20Alkyl-carbonyl groups.
In another preferred embodiment, the thiophene-substituted pyrrolopyrroledione group has the structure shown in formula I:
in the formula, R5As defined above; the wavy line indicates the portion bonded to other groups.
In another preferred embodiment, X is S or O.
In another preferred embodiment, the compound of formula a is a compound selected from the group consisting of:
in the formula, R1、R2、R5As defined above.
In another preferred embodiment, R1Is fluorine atom or H.
In another preferred embodiment, R2Is H, bromine atom, substituted or unsubstituted thiophene, wherein said "substituted" means that one or more H in the group is substituted by a substituent selected from the group consisting of: halogen, C1-30Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-20Alkyl radical, C1-20Alkyl-carbonyl, formyl.
In another preferred embodiment, the compound of formula B is a compound selected from the group consisting of:
in the formula (II), R'1、R'2、R'3、R4、R5As defined above.
In another preferred embodiment, R1、R2、R'1、R'2、R'3Each independently is selected from: H. cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, C substituted by halogen or phenyl2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C = C-COOC1-20An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-20Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
In another preferred embodiment, R1、R2、R'1、R'2、R'3Each independentlyIs selected from: H. halogen, C1-8Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, C substituted by halogen or phenyl2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C = C-COOC1-20An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-20Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
In another preferred embodiment, R4Selected from: cyano, halogen, C1-10Alkyl, halogenated C1-10Alkyl radical, C2-10Alkenyl, halogenated C2-10Alkenyl radical, C2-10Alkynyl, halogenated C2-10Alkynyl, C1-10Alkoxy, halogenated C1-10Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C = C-COOC1-10Alkyl, wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl.
In another preferred embodiment, R4Preferably cyano, halogen, C1-10Alkyl, halogenated C1-10Alkyl radical, C2-10Alkenyl, halogenated C2-10Alkenyl radical, C2-10Alkynyl, halogenated C2-10Alkynyl, C1-10Alkoxy, halogenated C1-10An alkoxy group.
In another preferred embodiment, R5Selected from: H. c1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, substituted benzyl; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
In another preferred embodiment, R5Selected from: c1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, substituted or unsubstituted phenyl.
In another preferred embodiment, R5Selected from: c1-15Alkyl, halogenated C1-15Alkyl radical, C2-15Alkenyl, halogenated C2-15Alkenyl radical, C2-15Alkynyl, halogenated C2-15Alkynyl, substituted or unsubstituted phenyl.
In another preferred embodiment, said halogenated C1-20Alkyl being fluoro C1-20An alkyl group; preferably perfluoro substituted C1-20An alkyl group.
In another preferred embodiment, the reaction is carried out at a temperature of 40 ℃ to 140 ℃.
In another preferred embodiment, the molar ratio of the compound of formula A, the palladium salt, the oxidant and the compound of formula B is 1-8: 0.001-1: 0.1-8: 1-8.
In another preferred embodiment, the molar percentage of the palladium salt is between 1% and 100%, preferably between 1 and 10%, of the molar amount of the compound of formula a.
In another preferred embodiment, the reaction concentration of the compound of formula A and/or the compound of formula B is 0.01-3 mmol/mL; preferably 0.1-0.8 mmol/mL.
In another preferred embodiment, the molar ratio of the compound of formula a, the oxidizing agent and the compound of formula B is 1 to 3: 0.1-4: 1-3.
In another preferred embodiment, the molar ratio of the compound of formula A, the palladium salt, the oxidant and the compound of formula B is 1-8: 0.02-0.1: 0.1-8: 1-8.
In another preferred embodiment, the palladium salt is selected from: PdM2、PdLnCl2、Pd(PPh3)4、Pd2(dba)3Or a combination thereof; wherein,
m is acetate, trifluoroacetate, triflate, pivalate or halogen;
l is a ligand selected from the group consisting of: an allyl, monodentate or bidentate phosphine ligand;
1<n<2。
in another preferred embodiment, the mono-or bidentate phosphine ligand is selected from the group consisting of: triphenylphosphine, tricyclohexylphosphine, 1 '-bis (diphenylphosphino) ferrocene (dppf), 1' -bis (diphenylphosphino) methane (dppm), 1, 2-bis (diphenylphosphino) ethane (dppe) or 1, 4-bis (diphenylphosphino) butane (dppb).
In another preferred embodiment, the oxidizing agent is selected from: a silver salt, a copper salt, p-benzoquinone, a p-benzoquinone derivative, oxygen, or a combination thereof.
In another preferred embodiment, the silver salt is selected from: silver fluoride, silver acetate, silver trifluoroacetate, silver carbonate, silver triflate, silver perchlorate, silver nitrate, silver oxide, or combinations thereof.
In another preferred embodiment, the copper salt is selected from: copper oxide, copper acetate, copper halide, copper carbonate, or combinations thereof.
In another preferred embodiment, the p-benzoquinone derivative comprises: 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ).
In another preferred embodiment, the inert solvent is selected from: n-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone, 1, 4-dioxane, N-dimethylacetamide, or a combination thereof.
In a second aspect, the present invention provides a compound of the formula selected from the group consisting of:
in a third aspect, the present invention provides a compound of formula ii, having the structure:
in the formula, R8Is H or a fluorine atom; r9Is halogen;
p is S, O, Se or NR10(ii) a Wherein R is10Is H, C1-20Alkyl or halogenated C1-20An alkyl group.
In another preferred embodiment, P is S or NR10And R is10Is C1-20An alkyl group.
In another preferred embodiment, R9Is a bromine atom.
In another preferred embodiment, P is NR10And R is10Is C1-20An alkyl group.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The invention provides a preparation method of fluorobenzene heterocycle-heteroaromatic ring and derivatives thereof through long-term intensive research, which is a simple method for synthesizing fluorobenzene heterocycle-heteroaromatic ring and derivatives thereof through direct functionalization of two carbon-hydrogen bonds in the presence of an oxidant by taking palladium salt as a catalyst. The method has the advantages of simple and easily obtained raw materials, small using amount of the catalyst, wide application range of the substrate, simple and convenient operation, high reaction efficiency and the like. On this basis, the inventors have completed the present invention.
Term(s) for
As used herein, the term "C1-30Alkyl "means a straight or branched chain alkyl group having 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or the like.
The term "C2-30Alkenyl "means a straight or branched chain alkenyl group having 2 to 30 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, or the like.
The term "C2-30Alkynyl "means straight or branched chain alkynyl having 2 to 30 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, or the like.
The term "C1-30Alkoxy "means a straight or branched chain alkoxy group having 1 to 30 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
The term "halogenated" means that the H in the group is substituted by one or more halogen atoms, which may be the same or different, such as trifluoromethyl, pentafluoroethyl, trifluoromethoxy, difluorovinyl, or the like.
The term "C1-30Alkyl-carbonyl "means C1-30Alkyl- (C = O) -.
The term "benzoheterocyclyl" refers to fused rings in which two or more rings containing benzene rings are fused together, including benzo 5-membered heterocyclic rings, benzo 6-membered heterocyclic rings, or 5-membered heterocyclic-benzene ring-5-membered heterocyclic rings or 5-membered heterocyclic-benzene ring-6-membered heterocyclic rings, preferably benzo 5-membered heterocyclic rings or 5-membered heterocyclic-benzene ring-5-membered heterocyclic rings, such as benzothiophene rings, benzopyrrole rings, benzofuran rings, thiophene-benzene ring-thiophene rings.
As used herein, "fluorobenzene heterocycle-heteroaromatic ring structure", "fluorobenzene heterocycle-heteroaromatic ring derivative", "fluorobenzene heterocycle-heteroaromatic ring building block compound", or "fluorobenzene heterocycle-heteroaromatic ring building block", used interchangeably, refer to a compound of formula C.
Preparation method
The invention provides a preparation method of fluorobenzene heterocycle-heteroaromatic ring and derivatives thereof. Preferably, the method comprises the steps of:
reacting a compound of formula A (namely fluoro benzo heterocycle or a derivative thereof) with a compound of formula B (namely a heteroaromatic ring compound) in an inert solvent at a certain temperature (such as 40-140 ℃, preferably 60-100 ℃) by using a palladium salt as a catalyst and in the presence of an oxidant for a period of time (such as 1-20 hours or 5-10 hours) to form a compound of formula C (namely fluoro benzo heterocycle-heteroaromatic ring building block and a derivative thereof);
in the formulae, R1、R2、R'1、R'2、R'3X, Y are as previously defined.
Wherein the compound of formula a is a compound selected from the group consisting of:
in the formulae, R1、R2、R5As described above.
More preferably, said compound of formula a is a compound selected from the group consisting of:
wherein said compound of formula B is preferably a compound selected from the group consisting of:
of formulae (II) to (III)'1、R'2、R'3、R4、R5As described above.
More preferably, said compound of formula B is a compound selected from the group consisting of:
the compounds of formula A and formula B of the present invention may be prepared by methods commercially available or well known to those skilled in the art to which the present invention pertains. For example, by the following method, however, the specific conditions of the method, such as reactants, solvent, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation.
The compounds of formula a and B according to the invention can also be conveniently prepared by optionally combining the various synthetic methods described in the present specification or known in the art, such combinations being readily carried out by those skilled in the art to which the invention pertains.
A preferred synthetic route for a class of compounds of formula A-1 is shown below:
reagents and conditions:
a)SOCl2、Et3N、CHCl3、60-70℃、5h。
a preferred synthetic route for a class of compounds of formula A-2 is shown below:
reagents and conditions:
b)NaNO2、HOAc/H2O；
c)R5Br、t-BuOK、MeOH、60-70℃、24h，R5as defined above.
Among them, the compounds of formula D can be prepared by a patent (see US5514680a 1), and a preferred synthetic method is as follows:
reagents and conditions:
d)Br2、HOAc；e)SnCl2、EA/EtOH。
the palladium salt used as the catalyst may be selected from those known to those skilled in the art, and a preferred class of palladium salts includes, but is not limited to: PdM2、PdLnCl2、Pd(PPh3)4Or Pd2(dba)3(ii) a Wherein M is acetate, trifluoroacetate, triflate, pivalate or halogen (such as chloride ion, bromide ion, etc.); l is a ligand selected from the group consisting of: allyl, monodentate or bidentate phosphine ligands, a preferred class of monodentate or bidentate phosphine ligands includes, but is not limited to: triphenylphosphine, 1 '-bis (diphenylphosphino) ferrocene (dppf), 1' -bis (diphenylphosphino) methane (dppm), 1, 2-bis (diphenylphosphino) ethane (dppe) or 1, 4-bis (diphenylphosphino) butane (dppb); n is more than 1 and less than 2.
"PPh" as described herein3"is triphenylphosphine; "dba" is dibenzylidene acetone. Preferably, the palladium salt is palladium trifluoroacetate.
In the reaction system, the mole percentage of the palladium salt used is 1-100%, preferably 1-10% of the mole amount of the compound of formula A.
The oxidant of the invention comprises: oxygen, silver salts (e.g., silver fluoride, silver acetate, silver trifluoroacetate, silver carbonate, silver triflate, silver nitrate, silver oxide, and like silver salts); copper salts (e.g., copper salts such as copper oxide, copper acetate, copper halide, and copper carbonate); p-benzoquinone or derivatives thereof (e.g., DDQ, etc.).
The reaction system may optionally further contain a base or a protonic acid. The protic acid preferably comprises an acid selected from the group consisting of: acetic acid, formic acid, propionic acid, adamantanic acid, pivalic acid, benzoic acid, and benzoic acid derivatives, or combinations thereof. Preferably, the benzoic acid derivative is C1-6Benzoic acid substituted with alkyl, nitro or phenyl. The base preferably comprises an inorganic base or an organic base, and the inorganic base comprises carbonate, phosphate and the like; the organic base comprises pyridine and derivatives thereof (such as 2-methylpyridine and other derivatives) and other organic amine compounds (such as triethylamine, diethylamine, diisopropylamine and the like)
The inert solvent includes a solvent selected from the group consisting of: n-methylpyrrolidone (NMP), N-dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone (DMPU), 1, 4-dioxane, N-dimethylacetamide, or a combination thereof. Preferably, dimethyl sulfoxide is used.
In the reaction system, the reaction concentration of the compound of the formula A or the compound of the formula B is 0.01-1 mmol/mL; preferably, it is 0.3 to 0.5 mmol/mL.
The compound of formula C prepared by the present invention can be further modified as required to prepare various functional compounds, such as materials for organic solar cells and red light emission.
The product prepared by the preparation method can be separated and purified by various methods, and the methods comprise the following steps: recrystallization, thin layer chromatography, column chromatography, etc. The above purification methods are all conventional in the art, and for example, when recrystallization is performed, a mixed solvent of a polar solvent and a nonpolar solvent, preferably a mixed solvent of ethyl acetate-petroleum ether, ethanol-petroleum ether, or the like, may be used. When thin layer chromatography and column chromatography are used, the developing solvent used may be a single solvent or a mixed solvent such as petroleum ether or a mixed solvent of ethyl acetate and petroleum ether.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
Compared with the prior art, the preparation method of the invention mainly has the following advantages:
(1) the method has the advantages of short reaction steps, simple and easily obtained raw materials and reagents, no need of pre-activation treatment, and higher economical efficiency and simplicity compared with the existing method.
(2) The method of the invention has the advantages of less catalyst consumption, wide substrate application range, simple and convenient operation, high reaction efficiency and suitability for industrial production, can avoid using highly toxic reagents,
(3) the fluorobenzene heterocycle-heteroaromatic ring and the derivative thereof prepared by the invention have wide application in photoelectric materials, luminescent agents, solar cells and other aspects.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
As used herein, "OAc" is acetate; "Tfa" is trifluoroacetate.
Purification was carried out by a method of post-treatment which is conventional in the art in the following examples.
Example 1
A three-necked flask was charged with Compound 1 (Compound 1 was prepared according to US5514680A1, 5.6g,25mmol), CHC13(150mL), triethylamine (11.4mL,4 equiv.) stirring for 15 minutes, and thionyl chloride (SOCl)27.2g,2equiv) was added slowly thereto and refluxed for 5 hours. Product 2(5.1g,81% yield) was a white solid obtained by column chromatography.1H NMR(300MHz,CDCl3)7.30(t,J=8.1Hz,1H).19F NMR(376MHz,CDCl3)-120.5(dd,J=19.9Hz,7.5Hz1F),-125.7(dd,J=19.7Hz,8.8Hz1F)。
Example 2
100mL of H in HOAc (2.4mL,40mmol)2Adding compound 3 into O solution, heating to dissolve completely, cooling to room temperature, and slowly adding NaNO2(1.52g in 20mL water) and then filtered to give Compound 4(2.3g,10mmol) was dissolved in 50mL methanol and tBuOK (1.15g,1.02equiv) and C were added under nitrogen8H17Br (1.95g,1.01 equiv). After stirring under reflux for 24 hours, the mixture was separated by column chromatography to obtain Compound 5(1.20g,35% yield) as a colorless liquid1H NMR(400MHz,CDCl3)7.55(dd,J=8.6Hz,7.0Hz,1H),4.70(t,J=7.4Hz,2H),2.10(m,2H),1.40-1.15(m,10H),0.86(t,J=6.8Hz,3H).19F NMR(376MHz,CDCl3)-128.9(dd,J=19.2Hz,6.8Hz1F),-129.7(dd,J=19.7Hz,8.8Hz1F)。
Example 3
In a three-necked flask was added compound 6(5.0g,25mmol), CHC13(150mL), triethylamine (11.4mL,4equiv). After stirring for 15 minutes, thionyl chloride (SOCl)27.2g,2equiv) was added slowly thereto and refluxed for 5 hours. Product 7(4.5g,78% yield) was a yellow solid and was obtained by column chromatography.
Example 4
Adding palladium salt, oxidant and compound 8 into a 25mL reaction tube, replacing with nitrogen for three times, adding the additive, injecting compound 9, and stirring at 80 ℃ for 6 hours to obtain compound C-1.1H NMR(400MHz,CDCl3)δ7.94(s,1H),2.65(t,J=7.6Hz,2H),1.66(m,2H),1.45-1.25(m,6H),0.90(t,J =7.0Hz,3H).19F NMR(376MHz,CDCl3)δ.120.3(d,J=19.0Hz,1F),-126.2(d,J=19.0Hz,1F)。
Wherein the amounts of the reactants and the yield of compound C-1 are shown in table 1:
TABLE 1
Example 5
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 10, stirring at 80 ℃ for 6 hours, gave compound C-2 in 73% yield.1H NMR(400MHz,CDCl3)δ8.01(d,J =4.2Hz,1H),7.21(d,J=4.2Hz,1H).19F NMR(376MHz,CDCl3)δ.120.1(d,J=19.2Hz,1F),-126.6(d,J=19.2Hz,1F)。
Example 6
To a 25mL reaction tube, add3.4mg(5mol%)Pd(OAc)2，Ag2CO3(0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 11, stirring at 80 ℃ for 6 hours, compound C-3 was obtained in 74% yield.1H NMR(400MHz,CDCl3)δ8.03(d,J=4.0Hz,1H),7.06(dd,J=4.0Hz,1.2Hz1H).19F NMR(376MHz,CDCl3)δ.120.1(d,J=19.0Hz,1F),-126.8(d,J=19.0Hz,1F)。
Example 7
To a 25mL reaction tube, 3.4mg (5mol%) Pd (OAc) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 12, stirring at 80 ℃ for 6 hours, gives Compound C-4 in 76% yield.1H NMR(400MHz,CDCl3)δ8.21(d,J=3.6Hz,1H),7.90(dd,J=4.2Hz,1.0Hz1H).3.95(s,3H).19F NMR(376MHz,CDCl3)δ.-119.9(d,J=17.7Hz,1F),-124.6(d,J=17.7Hz,1F)。
Example 8
To a 25mL reaction tube, 3.4mg (5mol%) Pd (Tfa)2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 13, stirring at 80 ℃ for 6 hours, gives Compound C-5 in 84% yield.1H NMR(400MHz,CDCl3)δ8.00(s,1H),3.92(s,3H),3.64(s,3H).19FNMR(376MHz,CDCl3)δ.-120.0(d,J=18.2Hz,1F),-124.7(d,J=18.2Hz,1F)。
Example 9
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 14, stirring at 80 ℃ for 6 hours, gives Compound C-6 in 74% yield.1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.32(d,J=4.0Hz1H),7.88(dd,J=4.0Hz,1.2Hz1H).19F NMR(376MHz,CDCl3)δ.-120.3(d,J=19.2Hz,1F),-124.9(d,J=19.2Hz,1F)。
Example 10
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), PhCOOH (0.8 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 15, stirring at 80 ℃ for 6 hours, gives Compound C-7 in 64% yield. 1H NMR (400MHz, CDCl3) δ 9.90(s,1H),8.21(d, J =4.0Hz1H),7.72(d, J =4.0Hz1H),7.46(dd, J =4.0Hz,1.2Hz1H),7.39(d, J =4.0Hz1H), 19F NMR (376MHz, CDCl3) δ -120.1(d, J =19.0Hz,1F), -125.5(d, J =19.0Hz, 1F).
Example 11
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1equiv), TFA (0.8 equiv), nitrogen were replaced three times and 1mL of Dimethylsulfoxide (DMSO) was added, 77. mu.L (0.40mmol) of Compound 16 was injected, and after stirring at 80 ℃ for 6 hours, Compound C-8 was obtained in 72% yield.1H NMR(400MHz,CDCl3)δ8.02(d,J=4.0Hz1H),6.89(m,1H),2.58(s,3H).19F NMR(376MHz,CDCl3)δ.-120.4(d,J=19.2Hz,1F),-127.7(d,J=19.2Hz,1F)。
Example 12
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 17, stirring at 80 ℃ for 6 hours, to give Compound C-9 in 86% yield.1H NMR(400MHz,CDCl3)δ8.48(s,1H),7.89(m,2H),7.41(m,2H).19F NMR(376MHz,CDCl3)δ.-120.4(d,J=18.4Hz,1F),-127.7(d,J=18.4Hz,1F)。
Example 13
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 18, stirring at 80 ℃ for 6 hours to give Compound C-10, and collectingThe ratio was 84%.1H NMR(400MHz,CDCl3)δ8.22(d,J=4.0Hz,1H),7.70(d,J=8.0Hz,1H),7.46-7.38(m,3H),7.34(d,J=7.2Hz,1H).19F NMR(376MHz,CDCl3)δ.-120.0(d,J=17.7Hz,1F),-127.4(d,J=17.7Hz,1F)。
Example 14
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 19, stirring at 80 ℃ for 6 hours, compound C-11 was obtained in 74% yield.1H NMR(400MHz,CDCl3)δ8.18(d,J=4.0Hz,1H),7.60-7.50(m,2H),7.40-7.34(m,4H).19FNMR(376MHz,CDCl3)δ.-120.2(d,J=19.2Hz,1F),-126.2(d,J=19.2Hz,1F)。
Example 15
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 20, stirring at 80 ℃ for 6 hours, compound C-12 was obtained in 53% yield.1H NMR(400MHz,CDCl3)δ8.00(s,2H),7.71(d,J=7.2Hz,1H),7.63(d,J=8.4Hz,1H),7.41(t,J=7.2Hz,1H),7.31(t,J=7.6Hz,1H).19F NMR(376MHz,CDCl3)δ.-119.9(d,J=17.7Hz,1F),-125.8(d,J=17.7Hz,1F)。
Example 16
To a 25mL reaction tube, 3.4mg (5mol%) Pd (Tfa)2Ag2O (0.8mmol), Compound 21(0.2mmol, 1 eq), after displacement with nitrogen three times, 1mL of dimethyl sulfoxide (DMSO) was added and Compound 22(0.80mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-13 in 64% yield.1H NMR(400MHz,CDCl3)δ7.94(s,1H),2.65(t,J=7.6Hz,4H),1.66(m,4H),1.45-1.27(m,12H),0.90(t,J=6.8Hz,6H).19F NMR(376MHz,CDCl3)δ.-118.1(s,2F)。
Example 17
To a 25mL reaction tube, 3.4mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.8mmol), Compound 23(1.2mmol, 1 equiv.), nitrogen substitution three times followed by addition of 1mL dimethyl sulfoxide (DMSO), injection of Compound 22(0.4mmol, 1 equiv.), and stirring at 80 ℃ for 10 hours gave Compound C-14 (i.e., Compound 21) in 71% yield.1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.60(t,J=8.4Hz,1H),2.65(t,J=7.6Hz,4H),1.66(m,2H),1.45-1.27(m,6H),0.90(t,J=6.8Hz,3H).19F NMR(376MHz,CDCl3)δ.-127.1(dd,J=17.1Hz,8.8Hz1F),-128.7(dd,J=16.9Hz,7.5Hz1F)。
Example 18
To a 25mL reaction tube, 3.4mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.8mmol), Compound 23(1.2mmol, 1 equiv.), nitrogen was substituted three times and 1mL of Dimethylsulfoxide (DMSO) was added, Compound 10(0.4mmol, 1 equiv.) was injected and stirred at 80 ℃ for 10 hours to give Compound C-15 in 69% yield.1H NMR(400MHz,CDCl3)δ8.01(t,J=4.0Hz,1H),7.64(dd,J=9.0Hz,7.4Hz,1H),7.20(dd,J=4.2Hz,1.0Hz,1H).19F NMR(376MHz,CDCl3)δ.-127.1(dd,J=12.6Hz,9.6Hz1F),-128.7(dd,J=16.2Hz,6.8Hz1F)。
Example 19
To a 25mL reaction tube, 3.4mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.8mmol), Compound 23(1.2mmol, 1 equiv.), nitrogen was replaced three times and then 1mL of Dimethylsulfoxide (DMSO) was added, and Compound 14(0.4mmol, 1 equiv.) was injected and stirred at 80 ℃ for 10 hours to give Compound C-16 in 47% yield.1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.34(d,J=4.0Hz,1H),7.89(dd,J=3.6Hz,1.2Hz1H),7.77(dd,J=8.8Hz,7.6Hz1H).19FNMR(376MHz,CDCl3)δ.-125.3(dd,J=16.4Hz,8.1Hz1F),-126.8(dd,J=16.9Hz,9.0Hz1F)。
Example 20
To a 25mL reaction tube, 3.4mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.8mmol), Compound 23(1.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of Compound 24(0.4mmol, 1 equiv.), stirring at 80 deg.C for 10 hours to give Compound C-17 in yield47%。1H NMR(400MHz,CDCl3)δ8.03(d,J=2.8Hz,1H),7.49(t,J=8.2Hz,1H),6.88(d,J=2.8Hz,1H),2.88(t,J=7.6Hz,2H),1.75(m,2H),1.50-1.25(m,6H),0.90(t,J=7.0Hz,3H).19F NMR(376MHz,CDCl3)-127.3(dd,J=17.1Hz,8.8Hz1F),-129.7(dd,J=16.9Hz,7.5Hz1F)。
Example 21
To a 25mL reaction tube, 3.4mg (5mol%) Pd (Tfa)2Ag2O (0.4mmol), Compound 8(0.4mmol, 4 equiv.) were purged with nitrogen three times, then 1mL of Dimethylsulfoxide (DMSO) was added, Compound 25(0.1mmol, 1 equiv.) was added, and the mixture was stirred at 80 ℃ for 10 hours to give Compound C-18 in a yield of 68%.1H NMR(400MHz,CDCl3)δ9.06(d,J=3.2Hz,1H),8.95(d,J=3.6Hz,1H),8.39(d,J=4.4Hz,1H),7.64(d,J=4.8Hz2H),7.27(d,J=4.8Hz2H),4.14(t,J=7.8Hz2H),4.05(t,J=8.0Hz2H),4.14(t,J=7.8Hz2H),1.90-1.60(m,4H),1.50-1.25(m,20H),0.86(t,J=7.4Hz6H).19F NMR(376MHz,CDCl3)δ.-120.1(d,J=18.6Hz1F),-124.0(d,J=18.6Hz1F)。
Example 22
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 26, stirring at 80 ℃ for 6 hours, compound C-19 was obtained in 45% yield.1H NMR(400MHz,CDCl3)δ8.20(d,J=4.0Hz,1H),7.34(d,J=3.6Hz,1H),7.31(d,J=4.4Hz,1H),7.08(dd,J=5.2Hz,3.6Hz,1H).19FNMR(376MHz,CDCl3)δ.-120.3(d,J=18.6Hz,1F),-126.7(d,J=18.6Hz,1F)。
Example 23
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound C-16(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 27, stirring at 80 ℃ for 6 hours, compound C-20, yield 61%.1H NMR(300MHz,CDCl3)δ9.97(s,1H),8.68(s,1H),8.25(d,J=4.2Hz,1H),7.78(d,J=3.6Hz,1H),7.36(d,J=4.2Hz,1H),4.20(d,J=14.1Hz,4H),1.90-1.30(m,18H),1.07(q,J=8.2Hz,6H),0.98(m,6H).19F NMR(282MHz,CDCl3)δ.-124.4(d,J=14.7Hz,1F),-126.3(d,J=14.7Hz,1F)。
Example 24
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound C-15(0.2mmol, 1 equiv.), nitrogen substitution three times, then 1mL dimethyl sulfoxide (DMSO) was added, 77. mu.L (0.40mmol) of Compound 27 was injected, and after stirring at 80 ℃ for 6 hours, Compound C-21 was obtained in 53% yield.1H NMR(400MHz,CDCl3)δ8.60(s,1H),7.88(d,J=4.0Hz,1H),7.35(dd,J=13.0Hz,1.4Hz,1H),7.08(d,J=4.0Hz,1H),4.20(d,J=3.6Hz,2H),4.15(d,J=4.4Hz,2H),1.90-1.35(m,18H),1.15-0.95(m,12H).19F NMR(376MHz,CDCl3)δ.-126.3(d,J=13.5Hz,1F),-127.8(d,J=13.5Hz,1F)。
Example 25
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 28(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 22, stirring at 80 ℃ for 6 hours, compound C-22 was obtained in 66% yield.1H NMR(400MHz,CDCl3)δ7.89(s,1H),4.75(t,J=7.6Hz,2H),2.64(t,J=7.6Hz,2H),2.14(m,2H),1.65(m,2H),1.50-1.20(m,16H),0.95-0.84(m,6H).19F NMR(376MHz,CDCl3)δ.-128.8(d,J=18.4Hz,1F),-132.4(d,J=18.4Hz,1F)。
Example 26
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 28(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 10, stirring at 80 ℃ for 6 hours, compound C-23 was obtained in 64% yield.1H NMR(400MHz,CDCl3)δ7.98(d,J=4.0Hz,1H),7.15(dd,J=4.0Hz,1.2Hz,1H),4.75(t,J=7.4Hz,2H),2.14(m,2H),1.50-1.20(m,12H),0.87(t,J=6.8Hz,3H).19F NMR(282MHz,CDCl3)δ.-129.1(d,J=18.8Hz,1F),-132.5(d,J=18.8Hz,1F)。
Example 27
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 28(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 14, stirring at 80 ℃ for 6 hours, compound C-24, 62% yield.1H NMR(300MHz,CDCl3)δ10.00(s,1H),8.28(d,J=4.2Hz,1H),7.83(dd,J=4.0Hz,1.6Hz,1H),4.77(t,J=7.4Hz,2H),2.15(m,2H),1.45-1.20(m,10H),0.85(t,J=6.6Hz,3H).19F NMR(282MHz,CDCl3)δ.-128.7(d,J=19.7Hz,1F),-132.5(d,J=19.7Hz,1F)。
Example 28
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), Compound 8(0.2mmol, 1 equiv.), nitrogen substitution three times, addition of 1mL dimethyl sulfoxide (DMSO), injection of 77. mu.L (0.40mmol) of Compound 29, stirring at 80 ℃ for 6 hours, compound C-25, 77% yield.1H NMR(300MHz,CDCl3)δ8.16(d,J=4.2Hz,1H),7.20(dd,J=3.9Hz,1.2Hz,1H),7.13(d,J=3.6Hz,1H),6.73(d,J=3.3Hz,1H),2.82(t,J=7.5Hz,2H),1.70(m,2H),1.50-1.26(m,6H),0.90(t,J=6.8Hz,3H).19F NMR(376MHz,CDCl3)δ.-125.2(d,J=18.2Hz,1F),-131.7(d,J=18.2Hz,1F)。
Example 29
To a 25mL reaction tube, 1.7mg (2.5mol%) Pd (Tfa) was added2，Ag2O (0.4mmol), compound 8(0.2mmol,1 equivalent), nitrogen substitution was carried out three times, 1mL of dimethyl sulfoxide (DMSO) was added, 77 μ L (0.40mmol) of compound 30 was injected, and after stirring at 80 ℃ for 6 hours, compound C-26 was obtained in 78% yield.1H NMR(300MHz,CDCl3)δ8.05(d,J=3.9Hz,1H),7.10(d,J=4.2Hz,1H),7.07(d,J=3.6Hz,1H),6.68(d,J=3.9Hz,1H),2.74(d,J=6.9Hz,2H),1.60(m,1H),1.45-1.28(m,8H),0.91(t,J=7.4Hz,6H).19F NMR(376MHz,CDCl3)δ.-125.2(d,J=18.8Hz,1F),-131.5(d,J=18.8Hz,1F)。
Example 30
To a 25mL reaction tube, 3.4mg (5mol%) Pd (Tfa)2Ag2O (0.8mmol), Compound 31(0.2mmol, 1 eq), after nitrogen substitution three times, 1mL of dimethyl sulfoxide (DMSO) was added and Compound 32(0.80mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-27 in 68% yield.1H NMR(400MHz,CDCl3)δ7.85(s,2H),2.56(d,J=7.6Hz,4H),7.30(t,J=7.6Hz,8H),1.69(m,2H),1.45-1.25(m,16H),0.93(t,J=7.8Hz,12H).19F NMR(376MHz,CDCl3)δ128.0。
Example 31
To a 25mL reaction tube, 2.24mg (5mol%) Pd (OAc) was added2AgOAc (0.8mmol), Compound 33(0.2mmol, 1 eq), after displacement with nitrogen three times, 2mL of dimethyl sulfoxide (DMSO) was added and Compound 22(0.40mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-28 in 42% yield.1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.85(dd,J=9.4Hz,5.0Hz,1H),7.51(dd,J=11.4Hz,9.4Hz,1H),2.65(t,J=7.6Hz,2H),1.66(m,2H),1.45-1.30(m,6H),0.90(t,J=7.0Hz,3H).19F NMR(376MHz,CDCl3)δ.-108.3(q,J=5.4Hz,1F)。
Example 32
To a 25mL reaction tube, 2.24mg (5mol%) Pd (OAc) was added2AgOAc (0.8mmol), Compound 33(0.2mmol, 1 eq), after displacement with nitrogen three times, 2mL of dimethyl sulfoxide (DMSO) was added and Compound 17(0.40mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-29 in 45% yield.1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.85(dd,J=9.0Hz,4.8Hz,1H),7.92(m,2H),7.59(dd,J=11.4Hz,9.0Hz,1H),7.41(m,2H).19F NMR(376MHz,CDCl3)δ.-107.2(q,J=5.4Hz,1F)。
Example 33
To a 25mL reaction tube, 2.24mg (5mol%) Pd (OAc) was added2AgOAc (0.8mmol), Compound 33(0.2mmol, 1 eq), after displacement with nitrogen three times, 2mL of dimethyl sulfoxide (DMSO) was added and Compound 18(0.40mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-30 in 47% yield.1H NMR(400MHz,CDCl3)δ8.25(d,J=4.0Hz,1H),7.85(q,J=4.7Hz,1H),7.72(d,J=7.2Hz,2H),7.54(dd,J=11.2Hz,9.2Hz,1H),7.46-7.38(m,3H),7.32(t,J=7.4Hz,1H).19F NMR(376MHz,CDCl3)δ.-108.3(q,J=5.5Hz,1F)。
Example 34
To a 25mL reaction tube, 2.24mg (5mol%) Pd (OAc) was added2AgOAc (0.8mmol), Compound 34(0.2mmol, 1 eq), after displacement with nitrogen three times, 2mL of dimethyl sulfoxide (DMSO) was added and Compound 11(0.40mmol) was injected and stirred at 80 ℃ for 10 hours to give Compound C-31 in 47% yield.1HNMR(400MHz,CDCl3)δ8.01(d,J=4.0Hz,1H),7.80(d,J=11.2Hz,1H),7.04(dd,J=4.4Hz,1.2Hz,1H).19F NMR(376MHz,CDCl3)δ.-107.8(d,J=10.9Hz,1F)。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (21)
1. A method of preparing a compound of formula C, comprising the steps of:
reacting a compound of formula A with a compound of formula B in an inert solvent in the presence of an oxidant using a palladium salt as a catalyst to form a compound of formula C;
in the above-mentioned formulas, the first and second substrates,
R1、R'1、R'2、R'3each independently of the other being H, cyano, halogen, C1-30Alkyl, halogenated C1-30Alkyl radical, C2-30Alkenyl, halogenated C2-30Alkenyl radical, C2-30Alkynyl, C substituted by halogen or phenyl2-30Alkynyl, C1-30Alkoxy, halogenated C1-30Alkoxy, -CONR6R7、-COOC1-30Alkyl radical, C1-30Alkyl-carbonyl, formyl, thiophene-substituted pyrrolopyrroledione, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C ═ C-COOC1-30An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-30Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-20Alkyl radical, C1-20Alkyl-carbonyl or formyl;
R2is bromine; or,
R'1and R'2Or R'2And R'3Together with the adjacent rings:
(a) a benzoheterocyclic group, or
(b) By one or more R4Substituted benzoheterocyclyl, wherein R4Selected from: cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, -CONR6R7、-COOC1-20Alkyl radical, C1-20Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C ═ C-COOC1-20Alkyl, wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl;
x is S, O, or NR5Y is S, O, Se, Te, Ga or NR5(ii) a Wherein R is5Is selected from: H. cyano radicals, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, -COOC1-20Alkyl radical, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C ═ C-COOC1-10Alkyl, substituted or unsubstituted benzyl; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl;
R6、R7each independently of the other being H, cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, -COOC1-20Alkyl radical, C1-20An alkyl-carbonyl group, which is a carbonyl group,
wherein the reaction is carried out at 40-140 ℃;
the molar ratio of the compound of formula A, the palladium salt, the oxidant and the compound of formula B is 1-8: 0.001-1: 0.1-8: 1 to 8;
the mole percentage of the palladium salt is 1 to 100 percent of the mole amount of the compound of the formula A;
the reaction concentration of the compound of the formula A and/or the compound of the formula B is 0.01-3 mmol/mL;
the palladium salt is selected from: PdM2、PdLnCl2、Pd(PPh3)4、Pd2(dba)3Or a combination thereof; wherein M is acetate, trifluoroacetate, triflate, pivalate or halogen; l is a ligand selected from the group consisting of: an allyl, monodentate or bidentate phosphine ligand; 1<n<2; the mono-or bidentate phosphine ligand is selected from: triphenylphosphine, tricyclohexylphosphine, 1 '-bis (diphenylphosphino) ferrocene, 1' -bis (diphenylphosphino) methane, 1, 2-bis (diphenylphosphino) ethane or 1, 4-bis (diphenylphosphino) butane;
the oxidant is selected from: a silver salt, a copper salt, p-benzoquinone, a p-benzoquinone derivative, oxygen, or a combination thereof, said silver salt selected from the group consisting of: silver fluoride, silver acetate, silver trifluoroacetate, silver carbonate, silver triflate, silver perchlorate, silver nitrate, silver oxide, or a combination thereof; the copper salt is selected from: copper oxide, copper acetate, copper halide, copper carbonate, or combinations thereof;
the inert solvent is selected from: n-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone, 1, 4-dioxane, N-dimethylacetamide, or a combination thereof.
2. The method of claim 1, wherein the thiophene-substituted pyrrolopyrroledione group has the structure of formula I:
in the formula, R5As defined above; the wavy line indicates the portion bonded to other groups.
3. The method of claim 1, wherein X is S or O.
4. The method of claim 1, wherein the compound of formula a is a compound selected from the group consisting of:
in the formula, R1、R2、R5As defined in claim 1.
5. The method of claim 1, wherein R is1Is a fluorine atom.
6. The method of claim 1, wherein R is1Is H.
7. The method of claim 1, wherein the compound of formula B is a compound selected from the group consisting of:
in the formula (II), R'1、R'2、R'3、R4、R5As defined in claim 1.
8. The method of claim 1, wherein R is1、R'1、R'2、R'3Each independently is selected from: H. cyano, halogen, C1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, C substituted by halogen or phenyl2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C ═ C-COOC1-20An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-20Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
9. The method of claim 1, wherein R is1、R'1、R'2、R'3Each independently is selected from: H. halogen, C1-8Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, C substituted by halogen or phenyl2-20Alkynyl, C1-20Alkoxy, halogenated C1-20Alkoxy, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C ═ C-COOC1-20An alkyl group; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-20Alkyl radical, C1-20Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
10. The method of claim 1, wherein R is4Selected from: cyano, halogen, C1-10Alkyl, halogenated C1-10Alkyl radical, C2-10Alkenyl, halogenated C2-10Alkenyl radical, C2-10Alkynyl, halogenated C2-10Alkynyl, C1-10Alkoxy, halogenated C1-10Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl, formyl, substituted or unsubstituted phenyl, substituted or unsubstituted-C ═ C-COOC1-10Alkyl, wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-10Alkyl radical, C1-10Alkyl-carbonyl or formyl.
11. The method of claim 1, wherein R is4Selected from cyano, halogen, C1-10Alkyl, halogenated C1-10Alkyl radical, C2-10Alkenyl, halogenated C2-10Alkenyl radical, C2-10Alkynyl, halogenated C2-10Alkynyl, C1-10Alkoxy, halogenated C1-10An alkoxy group.
12. The method of claim 1, wherein R is5Selected from: H. c1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, substituted benzyl; wherein said "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Alkoxy, -CONR6R7、-COOC1-8Alkyl radical, C1-8Alkyl-carbonyl, formyl.
13. The method of claim 1, wherein R is5Selected from: c1-20Alkyl, halogenated C1-20Alkyl radical, C2-20Alkenyl, halogenated C2-20Alkenyl radical, C2-20Alkynyl, halogenated C2-20Alkynyl, substituted or unsubstituted phenyl.
14. The method of claim 1, wherein R is5Selected from: c1-15Alkyl, halogenated C1-15Alkyl radical, C2-15Alkenyl, halogenated C2-15Alkenyl radical, C2-15Alkynyl, halogenated C2-15Alkynyl, substituted or unsubstituted phenyl.
15. The method of claim 1, wherein said halogenated C is1-20Alkyl being fluoro C1-20An alkyl group.
16. The method of claim 1 or 15, wherein said halogenated C is1-20Alkyl being perfluorinated C1-20An alkyl group.
17. The method of claim 1, wherein the palladium salt is present in a molar percentage of 1 to 10% of the molar amount of the compound of formula a.
18. The method of claim 1, wherein the compound of formula a and/or the compound of formula B is reacted at a concentration of 0.1 to 0.8 mmol/mL.
19. The method of claim 1, wherein the molar ratio of the compound of formula a, the oxidizing agent, and the compound of formula B is 1 to 3: 0.1-4: 1-3.
20. The method of claim 1, wherein the molar ratio of the compound of formula a, the palladium salt, the oxidant, and the compound of formula B is 1-8: 0.02-0.1: 0.1-8: 1-8.
21. The method of claim 1, wherein the compound of formula C is:
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