CN109867694A - A kind of synthetic method of the 7- alkynyl Benzazole compounds of oxygen guiding - Google Patents
A kind of synthetic method of the 7- alkynyl Benzazole compounds of oxygen guiding Download PDFInfo
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- CN109867694A CN109867694A CN201910161645.6A CN201910161645A CN109867694A CN 109867694 A CN109867694 A CN 109867694A CN 201910161645 A CN201910161645 A CN 201910161645A CN 109867694 A CN109867694 A CN 109867694A
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- indoles
- butyl
- phosphine oxide
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 10
- 239000001301 oxygen Substances 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 27
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 12
- -1 alkynes halogen Chemical class 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 150000002940 palladium Chemical class 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 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 16
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052802 copper Inorganic materials 0.000 claims description 16
- 239000010949 copper Substances 0.000 claims description 16
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 16
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 15
- 238000011097 chromatography purification Methods 0.000 claims description 15
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 15
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 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 description 5
- 239000000126 substance Substances 0.000 claims description 5
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 229940096017 silver fluoride Drugs 0.000 claims description 2
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229930008407 benzylideneacetone Natural products 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 claims 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006880 cross-coupling reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
- 239000000047 product Substances 0.000 description 54
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 37
- 229910052799 carbon Inorganic materials 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 26
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 26
- 229910052698 phosphorus Inorganic materials 0.000 description 26
- 239000011574 phosphorus Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 15
- 150000001345 alkine derivatives Chemical class 0.000 description 14
- 239000012046 mixed solvent Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000004679 31P NMR spectroscopy Methods 0.000 description 13
- 238000007445 Chromatographic isolation Methods 0.000 description 13
- 238000012512 characterization method Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 12
- 150000002475 indoles Chemical class 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 7
- 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 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 238000005905 alkynylation reaction Methods 0.000 description 4
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QZOPRMWFYVGPAI-UHFFFAOYSA-N 1-chloroindole Chemical class C1=CC=C2N(Cl)C=CC2=C1 QZOPRMWFYVGPAI-UHFFFAOYSA-N 0.000 description 2
- OHGRDCDSBYWPEL-UHFFFAOYSA-N 1-fluoroindole Chemical class C1=CC=C2N(F)C=CC2=C1 OHGRDCDSBYWPEL-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QQSIRURWBGEHFS-UHFFFAOYSA-N ditert-butyl(oxo)phosphanium Chemical compound CC(C)(C)[P+](=O)C(C)(C)C QQSIRURWBGEHFS-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 2
- MXQJQZOSVMJABL-UHFFFAOYSA-N 1-bromoindole Chemical class C1=CC=C2N(Br)C=CC2=C1 MXQJQZOSVMJABL-UHFFFAOYSA-N 0.000 description 1
- LJFVSIDBFJPKLD-UHFFFAOYSA-N 4-phenylmethoxy-1h-indole Chemical class C=1C=CC=2NC=CC=2C=1OCC1=CC=CC=C1 LJFVSIDBFJPKLD-UHFFFAOYSA-N 0.000 description 1
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 description 1
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- MCRSZLVSRGTMIH-UHFFFAOYSA-N ditert-butyl(chloro)phosphane Chemical compound CC(C)(C)P(Cl)C(C)(C)C MCRSZLVSRGTMIH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 108700009872 mild silver Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003004 phosphinoxides Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of the 7- alkynyl Benzazole compounds of oxygen guiding.The synthetic method are as follows: in the reactor, di-t-butyl (1 is addedHIndoles -1- base) phosphine oxide-type compound, alkynes halogen, palladium salt catalyst, oxidant, ligand and solvent, it is stirred to react at 80 ~ 100 DEG C, reaction solution is isolated and purified, and 7- alkynyl Benzazole compounds are obtained.The method of the present invention has developed di-t-butyl (1HIndoles -1- base) phosphine oxide and alkynes halogen cross-coupling reaction, construct a series of 7- alkynyl Benzazole compounds of highly functionals, have high step economy and Atom economy.In addition, raw material is simple and easy to get, safe operation, regioselectivity are good and substrate universality is extensively the main feature of reaction.
Description
Technical field
The invention belongs to 7- alkynyl Benzazole compounds fields, and in particular to a kind of 7- alkynyl indoles chemical combination of oxygen guiding
The synthetic method of object.
Background technique
Benzazole compounds have very important biology and pharmacological activity, such as anticancer, antibacterial, anti-hypertension etc..It is special
Chemical property and bioactivity Benzazole compounds are concerned in dyestuff, food, agricultural, medicine and other fields.Therefore
It is particularly significant in synthesis chemistry to synthesize and modify this heterocyclic compounds.Alkynes is as the weight in materials chemistry and organic chemistry
Structural motif is wanted, is the superior reacting precursor for participating in multiclass conversion, different location is synthesized using more effective and more direct method
Substituted alkynyl indole structure has received widespread attention.In traditional synthetic method, the building master of alkynyl indole derivatives
It to be completed by the C-H halogenation of indoles and further cross-coupling reaction.In recent years, the flourishing hair activated along with c h bond
Exhibition, the method for the direct C-H key function dough of indoles receive the favor of organic chemist due to being simple and efficient.Therefore, by mistake
The direct alkynylation reaction for crossing the non-activated c h bond selectivity of indoles of metal catalytic has great importance.
Due to Benzazole compounds have more reaction site, the site around nitrogen-atoms be mainly indoles carbon 2,
Carbon 3 and 7, carbon, multiple reaction site make the selective C-H activation to specified site very difficult.Wherein, indoles carbon 3 is upper
Cloud density is higher than the cloud density on other carbon, this makes 3 carbon be easier to that metalation occurs compared with other carbon,
To directly occur C-H alkynylation reaction (Q.Yin, H.F.T. Klare, M.Oestreich, Angew.Chem.Int.Ed.,
2017,56,3712;H.Wang,Z.Bai,T.Jiao, Z.Deng,H.Tong,G.He,Q.Peng,G.Chen,
J.Am.Chem.Soc.,2018,140,3542;T. Miao,P.Li,Y.Zhang,L.Wang,Org.Lett.,2015,17,
832.).3, carbon when indole substrate have steric group or make in nitrogen-atoms some nitrogenous compounds incorporated above of indoles
When for homing device, so that it may highly selective synthesis 2- alkynyl Benzazole compounds (L.Yang, L.Zhao, C.-J.Li,
Chem. Commun.,2010,46,4184;G.L.Tolnai,S.Ganss,J.P.Brand,Waser J.Org.Lett.
2013,15,112;Z.-Z.Zhang,B.Liu,C.-Y.Wang,B.-F,Shi.Org.Lett.,2015,17,4094; T.Li,
Z.Wang,W.-B.Qin,T.-B.Wen,ChemCatChem.,2016,8,2146;Z.Ruan,N. Sauermann,
E.Manoni,L.Ackermann,Angew.Chem.Int.Ed.,2017,129,3220.).But for 7, the carbon of indoles, by
In the cloud density of structure itself and the influence of steric hindrance, direct C-H alkynylation reaction has greatly challenge.Lead at present
Cross the choosing that C-H activation course obtains being all made of indoline in the report of 7- alkynyl indole derivatives as substrate reducing reaction
Selecting property, but such substrate also needs just obtain 7- alkynyl by being further oxidized after 7, carbon alkynylation reactions
Benzazole compounds (Y.Wu, Y.Yang, Bing Zhou, Y.Li, J.Org.Chem., 2015,80,1946;N.Jin,
C.Pan,H.Zhang,P. Xu,Y.Cheng,C.Zhu,Adv.Synth.Catal.,2015,357,1149.).These synthesis sides
Although method progress in terms of synthetic method is very big, reaction step is more, and operation is relatively complicated.Therefore, develop high selection
Property, the synthetic method of 7- alkynyl Benzazole compounds of step economy, green high-efficient are very necessary.
Summary of the invention
It is an object of the invention in view of the shortcomings of the prior art and insufficient, a kind of 7- alkynyl indoles of oxygen guiding is provided
The synthetic method of class compound.This method is original with di-t-butyl (1H- indoles -1- base) phosphine oxide and alkynes halogen simple and easy to get
Material, using common palladium salt as catalyst, as oxidant, toluene is solvent for mild silver salt and mantoquita, using weak coordination
Strategy of the oxygen as guiding base, selectively constructs the indole derivatives of 7 alkynyls, has Atom economy height, selection
Property it is single, safety and substrate applicability easy to operate are wide the advantages that, have good application prospect in actual production and research.
The purpose of the present invention is achieved through the following technical solutions.
A kind of synthetic method of the 7- alkynyl Benzazole compounds of oxygen guiding, comprises the following steps:
In the reactor, substrate di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound, alkynes halogen, palladium salt catalysis is added
Agent, oxidant, ligand and solvent are stirred to react at 80~100 DEG C, are cooled to room temperature after reaction, and product is pure through separating
Change, obtains the 7- alkynyl Benzazole compounds.
Further, the chemical equation of synthesis process is as follows:
In formula, R1Selected from hydrogen, 4- methyl, 4- methoxyl group, 4- Bian oxygroup, 4- fluorine, 4- chlorine, 4- bromine, 5- methyl, 5- methoxy
One or more of base, 5- fluorine, 5- chlorine and 3- methyl;
R2For one of triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBDMS);
X is chlorine, bromine or iodine.
Further, the palladium salt catalyst is palladium acetate, bis- (dibenzalacetone) palladiums and three (dibenzalacetones)
One or more of two palladiums, preferably tris(dibenzylideneacetone) dipalladium.
Further, the additional amount of the palladium salt catalyst and di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound
Molar ratio be 0.05~0.15:1, preferably 0.1:1.
Further, mole of the additional amount of the alkynes halogen and di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound
Than for 1.6~2.6:1, preferably 1.8:1.
Further, the oxidant is the mixture of silver salt and mantoquita, by silver fluoride, silver carbonate, copper oxide, wolframic acid silver
One or more of be mixed to get with trifluoromethayl sulfonic acid copper, the preferably mixture of silver carbonate and trifluoromethayl sulfonic acid copper.
Further, the additional amount of silver salt and di-t-butyl (1H- indoles -1- base) phosphinoxides chemical combination in the oxidant
The molar ratio of object is 1.0~2.0:1, preferably 1.8:1;The additional amount of mantoquita and di-t-butyl (1H- Yin in the oxidant
Diindyl -1- base) phosphine oxide-type compound molar ratio be 1.0~2.0:1, preferably 1.5:1.
Further, the ligand is 3- chloropyridine or 2- bromopyridine.
Further, mole of the additional amount of the ligand and di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound
Than for 0.1~0.3:1, preferably 0.2:1.
Further, the solvent is toluene.
Further, the time being stirred to react is 90 DEG C.
Further, the time being stirred to react is 6~20 hours, preferably 8~12 hours.
Further, the operation isolated and purified are as follows: reaction solution is extracted with ethyl acetate, organic phase is merged, is used
Anhydrous magnesium sulfate dries, filters, and removes organic solvent under reduced pressure, obtains crude product, through column Chromatographic purification, obtains the 7- alkynyl indoles
Class compound.
Further, the eluent of column chromatography is the mixing of petroleum ether and ethyl acetate 5~50:1 by volume
The mixed solvent of solvent, preferably petroleum ether and ethyl acetate 10~30:1 by volume.
The reaction principle of synthetic method of the present invention is made in the steric effect using the di-t-butyl phosphine oxide on indole nitrogen
Activate 7, carbon of indoles to the property of can choose after oxygen and palladium coordination, to form hexatomic ring palladium intermediate, later alkynes halogen and its
Oxidation addition is carried out, then is eliminated through reduction, 7- alkynyl Benzazole compounds are obtained.
Compared with prior art, the invention has the following advantages and beneficial effects:
(1) present invention has developed the cross-coupling of di-t-butyl (1H- indoles -1- base) phosphine oxide and alkynes halogen under oxygen guiding
The synthetic method of reaction building 7- alkynyl Benzazole compounds, and basic material di-t-butyl therein (1H- indoles -1- base)
Phosphine oxide can have that raw material is simple and easy to get, safe operation is simple, item by cheap di-t-butylchlorophosphine and indole synthesis
The feature that part is mild, Atom economy is high;
(2) target product can be obtained without secondary oxidation in synthetic method of the present invention, novel and high-efficiency, while to functional group
Tolerance is good, thus is expected to be applied to actual industrial production and further derivatization.
Detailed description of the invention
Fig. 1, Fig. 2 and Fig. 3 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 1 gained target product of embodiment respectively;
Fig. 4, Fig. 5 and Fig. 6 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 2 gained target product of embodiment respectively;
Fig. 7, Fig. 8 and Fig. 9 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 3 gained target product of embodiment respectively;
Figure 10, Figure 11 and Figure 12 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 4 gained target product of embodiment respectively;
Figure 13, Figure 14, Figure 15 and Figure 16 be respectively the hydrogen spectrogram of 5 gained target product of embodiment, carbon spectrogram, phosphorus spectrogram and
Fluorine spectrogram;
Figure 17, Figure 18 and Figure 19 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 6 gained target product of embodiment respectively;
Figure 20, Figure 21 and Figure 22 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 7 gained target product of embodiment respectively;
Figure 23, Figure 24 and Figure 25 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 8 gained target product of embodiment respectively;
Figure 26, Figure 27 and Figure 28 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 9 gained target product of embodiment respectively;
Figure 29, Figure 30, Figure 31 and Figure 32 are the hydrogen spectrogram, carbon spectrogram, phosphorus spectrogram of 10 gained target product of embodiment respectively
With fluorine spectrogram;
Figure 33, Figure 34 and Figure 35 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 11 gained target product of embodiment respectively;
Figure 36, Figure 37 and Figure 38 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 12 gained target product of embodiment respectively;
Figure 39, Figure 40 and Figure 41 are the hydrogen spectrogram, carbon spectrogram and phosphorus spectrogram of 13 gained target product of embodiment respectively.
Specific embodiment
Technical solution of the present invention is described in further detail below in conjunction with specific embodiments and drawings, but the present invention
Protection scope and embodiment it is without being limited thereto.
Embodiment 1
It is added in reaction tube 0.1 mM of di-t-butyl (1H- indoles -1- base) phosphine oxide, 0.01 mM of three (two Asia
Benzylacetone) two palladiums, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 3- chloropyridine,
0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred to react 12 at 90 DEG C, revolving speed 700rpm as solvent
After hour, stop heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merges organic phase and make
It is dried, filtered, is concentrated under reduced pressure with 0.5g anhydrous magnesium sulfate, then by column chromatographic isolation and purification, column chromatographic eluate used is
The petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 81%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product distinguish as shown in Figure 1, Figure 2 and Figure 3, structural characterization number
According to as follows:
1H NMR(400MHz,CDCl3) δ=7.58-7.53 (m, 2H), 7.29 (s, 1H), 7.11 (t, J=7.6 Hz,
1H), 6.69 (d, J=3.2Hz, 1H), 1.35 (d, J=14.4Hz, 18H), 1.17 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.3,133.6,131.5 (d, J=4.1Hz), 128.1 (d, J=
4.8Hz), 121.6,121.2,112.4,108.0 (d, J=5.1Hz), 107.5,94.8,39.2 (d, J=67.3 Hz),
27.1,18.8,11.6;
31P NMR(162MHz,CDCl3) δ=62.51-61.61 (m);
IR(KBr)νmax 2943,2868,1467,1387,1243,1129,993,879,738,659,474cm-1;
HRMS(ESI)Calcd for C27H45NOPSi[M+H]+:458.3003,Found 458.3008。
Infer that the structure of target product is as follows through above data:
Embodiment 2
It is added in reaction tube 0.1 mM of di-t-butyl (4- Methyl-1H-indole -1- base) phosphine oxide, 0.01 mmoles
That tris(dibenzylideneacetone) dipalladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM
3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred at 90 DEG C, revolving speed 700rpm as solvent
After mixing reaction 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic
It is dried, filtered mutually and using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then by column chromatographic isolation and purification, column chromatography used is washed
The petroleum ether that de- liquid is volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 82%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product distinguish as shown in Figure 4, Figure 5 and Figure 6, structural characterization number
According to as follows:
1H NMR(400MHz,CDCl3) δ=7.48 (d, J=7.6Hz, 1H), 7.29 (s, 1H), 6.91 (d, J=
7.2Hz, 1H), 6.71 (s, 1H), 2.50 (s, 3H), 1.35 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.0,133.6,131.0 (d, J=4.0Hz), 130.7,127.6 (d, J
=4.9Hz), 122.22,109.9,107.8,106.1 (d, J=5.1Hz), 93.8,39.2 (d, J=67.3Hz), 27.1,
18.8,11.6;
31P NMR(162MHz,CDCl3) δ=62.17-61.28 (m);
IR(KBr)νmax 2945,2867,1471,1355,1242,1122,1003,881,864,597,474cm-1;
HRMS(ESI)Calcd for C28H47NOPSi[M+H]+:472.3159,Found 472.3161。
Infer that the structure of target product is as follows through above data:
Embodiment 3
It is added in reaction tube 0.1 mM of di-t-butyl (4- methoxyl group -1H- indoles -1- base) phosphine oxide, 0.01 milli
Mole tris(dibenzylideneacetone) dipalladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM
3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred at 90 DEG C, revolving speed 700rpm as solvent
After mixing reaction 6 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic
It is dried, filtered mutually and using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then by column chromatographic isolation and purification, column chromatography used is washed
The petroleum ether that de- liquid is volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 72%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product distinguish as shown in Figure 7, Figure 8 and Figure 9, structural characterization number
According to as follows:
1H NMR(400MHz,CDCl3) δ=7.48 (d, J=7.6Hz, 1H), 7.29 (s, 1H), 6.91 (d, J=
7.2Hz, 1H), 6.71 (s, 1H), 2.50 (s, 3H), 1.35 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=153.3,139.5,134.9,126.6 (d, J=4.5Hz), 121.7 (d, J
=4.6Hz), 107.7,105.5,104.7 (d, J=4.9Hz), 102.2,92.4,55.3,39.2 (d, J=67.2Hz),
27.1,18.8,11.6;
31P NMR(162MHz,CDCl3) δ=62.17-61.28 (m);
IR(KBr)νmax 2941,2864,1482,1364,1272,1119,881,756,859,476cm-1;
HRMS(ESI)Calcd for C28H47NO2PSi[M+H]+:488.3108,Found 488.3111。
Infer that the structure of target product is as follows through above data:
Embodiment 4
It is added in reaction tube 0.1 mM of (4- (benzyloxy) -1H- indoles -1- base) di-t-butyl phosphine oxide, 0.01
MM tris(dibenzylideneacetone) dipalladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mmoles
That 3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are as solvent, at 80 DEG C, revolving speed 700rpm
After being stirred to react 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, is associated with
Machine phase is simultaneously dried, filtered using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then passes through column chromatographic isolation and purification, column chromatography used
Eluent is the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 82%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 10, Figure 11 and Figure 12, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.52-7.45 (m, 3H), 7.38 (t, J=7.3Hz, 2H), 7.34-7.30
(m, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 6.63 (d, J=8.2Hz, 1H), 5.18 (s, 2H), 1.35 (d, J=
14.8Hz,18H),1.16(s,21H);
13C NMR(100MHz,CDCl3) δ=152.5,139.6,137.0,134.9,128.5,127.9,127.3,
126.6 (d, J=4.7Hz), 122.1 (d, J=4.5Hz), 107.6,105.7,104.9 (d, J=5.1Hz), 103.6,
(92.6,70.0,39.2 d, J=67.2Hz), 27.1,18.8,11.6;
31P NMR(162MHz,CDCl3) δ=62.56-61.66 (m);
IR(KBr)νmax 2940,2864,1481,1366,1275,1117,1018,881,747,657,473cm-1;
HRMS(ESI)Calcd for C34H51NO2PSi[M+H]+:564.3421,Found 564.3429。
Infer that the structure of target product is as follows through above data:
Embodiment 5
It is added in reaction tube 0.1 mM of di-t-butyl (the fluoro- 1H- indoles -1- base of 4-) phosphine oxide, 0.01 mM three
(dibenzalacetone) two palladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 3- chlorine
Pyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred at 100 DEG C, revolving speed 700rpm as solvent
After reaction 20 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase
And dried, filtered using 0.5g anhydrous magnesium sulfate, it is concentrated under reduced pressure, then pass through column chromatographic isolation and purification, column chromatographic elution used
Liquid is the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 79%.
Hydrogen spectrogram, carbon spectrogram, phosphorus spectrogram and the fluorine spectrogram of gained target product are respectively such as Figure 13, Figure 14, Figure 15 and Figure 16
Shown, structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ=7.53-7.49 (m, 1H), 7.27 (s, 1H), 6.83-6.79 (m, 2H),
1.36 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=156.1 (d, J=248.8Hz), 140.5 (d, J=9.4Hz), 134.4
(d, J=7.4Hz), 128.0 (d, J=4.6Hz), 120.4 (dd, J=22.2,4.5Hz), 108.7 (d, J=4.0Hz),
107.1 (d, J=18.8Hz), 106.7,103.3 (d, J=5.0Hz), 94.2,39.3 (d, J=66.8 Hz), 27.1,18.8,
11.5;
31P NMR(162MHz,CDCl3) δ=63.40-62.48 (m);
19F NMR(376MHz,CDCl3) δ=- 120.43 (t, J=7.0Hz);
IR(KBr)νmax 2946,2871,1593,1479,1361,1247,1116,1007,882,799,662,
480cm-1;
HRMS(ESI)Calcd for C27H44FNOPSi[M+H]+:476.2908,Found 476.2910。
Infer that the structure of target product is as follows through above data:
Embodiment 6
It is added in reaction tube 0.1 mM of di-t-butyl (the chloro- 1H- indoles -1- base of 4-) phosphine oxide, 0.01 mM three
(dibenzalacetone) two palladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 2- bromine
Pyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene stir anti-as solvent at 90 DEG C, revolving speed 700rpm
After answering 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase simultaneously
It is dried, filtered, is concentrated under reduced pressure using 0.5g anhydrous magnesium sulfate, then pass through column chromatographic isolation and purification, column chromatographic eluate used
Target product, yield 60% are obtained for the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 17, Figure 18 and Figure 19, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.49 (d, J=8.0Hz, 1H), 7.34 (s, 1H), 7.12 (d, J=
8.0Hz, 1H), 6.84 (d, J=2.0Hz, 1H), 1.35 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.8,133.9,130.2 (d, J=4.1Hz), 128.7 (d, J=
4.5Hz), 126.3,121.5,111.2,106.6,106.2 (d, J=4.8Hz), 95.9,39.3 (d, J=66.6 Hz),
27.1,18.8,11.5;
31P NMR(162MHz,CDCl3) δ=63.49-62.60 (m);
IR(KBr)νmax 2946,2868,1468,1348,1239,1122,998,884,812,751,637,472 cm-1;
HRMS(ESI)Calcd for C27H43ClNNaOPSi[M+Na]+:514.2432,Found 514.2438。
Infer that the structure of target product is as follows through above data:
Embodiment 7
It is added in reaction tube 0.1 mM of di-t-butyl (the bromo- 1H- indoles -1- base of 4-) phosphine oxide, 0.01 mM three
(dibenzalacetone) two palladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 3- chlorine
Pyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene stir anti-as solvent at 90 DEG C, revolving speed 700rpm
After answering 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase simultaneously
It is dried, filtered, is concentrated under reduced pressure using 0.5g anhydrous magnesium sulfate, then pass through column chromatographic isolation and purification, column chromatographic eluate used
Target product, yield 53% are obtained for the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 20, Figure 21 and Figure 22, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.42 (d, J=8.2Hz, 1H), 7.34 (s, 1H), 7.28 (d, J=
8.0Hz, 1H), 6.80 (d, J=2.0Hz, 1H), 1.35 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.3,134.0,132.0 (d, J=3.9Hz), 128.6 (d, J=
4.6Hz), 124.7,115.0,111.7,108.1 (d, J=4.6Hz), 106.6,96.1,39.3 (d, J=66.6 Hz),
27.1,18.8,11.5;
31P NMR(162MHz,CDCl3) δ=63.60-62.70 (m);
IR(KBr)νmax 2942,2866,1466,1342,1238,1123,993,878,811,744,657,473 cm-1;
HRMS(ESI)Calcd for C27H43BrNNaOPSi[M+Na]+:558.1927,Found 558.1931。
Infer that the structure of target product is as follows through above data:
Embodiment 8
It is added in reaction tube 0.1 mM of di-t-butyl (5- Methyl-1H-indole -1- base) phosphine oxide, 0.01 mmoles
That tris(dibenzylideneacetone) dipalladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM
3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred at 90 DEG C, revolving speed 700rpm as solvent
After mixing reaction 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic
It is dried, filtered mutually and using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then by column chromatographic isolation and purification, column chromatography used is washed
The petroleum ether that de- liquid is volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 79%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 23, Figure 24 and Figure 25, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.37 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 6.61 (d, J=
2.0Hz, 1H), 2.38 (s, 3H), 1.34 (d, J=14.4Hz, 18H), 1.17 (s, 21H);
13C NMR(100MHz,CDCl3) δ=136.8,134.6,131.8 (d, J=4.2Hz), 130.9,128.2 (d, J
=4.9Hz), 121.3,111.9,107.6 (d, J=5.7Hz), 94.2,39.2 (d, J=67.5Hz), 27.1,20.7,
18.8,11.6;
31P NMR(162MHz,CDCl3) δ=61.91-61.02 (m);
IR(KBr)νmax 2944,2867,1466,1381,1239,1124,991,878,753,661,608,473 cm-1;
HRMS(ESI)Calcd for C28H47NOPSi[M+H]+:472.3159,Found 472.3163。
Infer that the structure of target product is as follows through above data:
Embodiment 9
It is added in reaction tube 0.1 mM of di-t-butyl (5- methoxyl group -1H- indoles -1- base) phosphine oxide, 0.01 milli
Mole tris(dibenzylideneacetone) dipalladium, 0.10 mM of silver carbonate, 0.20 mM of trifluoromethayl sulfonic acid copper, 0.02 mmoles
That 3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are as solvent, at 90 DEG C, revolving speed 700rpm
After being stirred to react 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, is associated with
Machine phase is simultaneously dried, filtered using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then passes through column chromatographic isolation and purification, column chromatography used
Eluent is the petroleum ether of volume ratio 10:1: ethyl acetate mixed solvent obtains target product, yield 48%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 26, Figure 27 and Figure 28, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.27 (d, J=2.4Hz, 1H), 7.19 (d, J=2.4Hz, 1H), 7.03
(d, J=2.4Hz, 1H), 6.61 (d, J=3.2Hz, 1H), 3.81 (s, 3H), 1.33 (d, J=14.4 Hz, 18H), 1.16 (s,
21H);
13C NMR(100MHz,CDCl3) δ=154.4,133.5,132.4 (d, J=4.2Hz), 128.8,121.8,
113.0,107.8 (dd, J=4.4,3.3Hz), 107.0,104.0 (d, J=1.4Hz), 94.8,39.2 (d, J=67.3Hz),
27.1,18.8,11.5;
IR(KBr)νmax 2045,2870,1679,1595,1467,1387,1228,1947,805,660,472 cm-1;
31P NMR(162MHz,CDCl3) δ=62.12-61.21 (m);
HRMS(ESI)Calcd for C28H47NO2PSi[M+H]+:488.3108,Found 488.3111。
Infer that the structure of target product is as follows through above data:
Embodiment 10
It is added in reaction tube 0.1 mM of di-t-butyl (the fluoro- 1H- indoles -1- base of 5-) phosphine oxide, 0.01 mM three
(dibenzalacetone) two palladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 2- bromine
Pyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene stir anti-as solvent at 90 DEG C, revolving speed 700rpm
After answering 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase simultaneously
It is dried, filtered, is concentrated under reduced pressure using 0.5g anhydrous magnesium sulfate, then pass through column chromatographic isolation and purification, column chromatographic eluate used
Target product, yield 56% are obtained for the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent.
Hydrogen spectrogram, carbon spectrogram, phosphorus spectrogram and the fluorine of gained target product are composed respectively such as Figure 29, Figure 30, Figure 31 and Figure 32 institute
Show, structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ=7.34 (s, 1H), 7.28 (d, J=9.6Hz, 1H), 7.20 (d, J=
8.0Hz, 1H), 6.65 (s, 1H), 1.34 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=157.7 (d, J=237.4Hz), 135.1,132.4 (dd, J=10.3,
4.1Hz), 129.7 (d, J=4.6Hz), 120.4 (d, J=25.6Hz), 113.3 (d, J=10.2Hz), 107.9 (t, J=
4.6Hz), 106.7 (d, J=22.9Hz), 106.2 (d, J=2.0Hz), 96.3,39.3 (d, J=67.0Hz), 27.1,
18.8,11.5;
31P NMR(162MHz,CDCl3)δ62.90-62.00(m);
19F NMR(376MHz,CDCl3) δ -123.43 (t, J=9.0Hz);
IR(KBr)νmax 2945,2870,1581,1467,1381,1234,1138,985,871,802,662,476 cm-1;
HRMS(ESI)Calcd for C27H44FNOPSi[M+H]+:476.2908,Found 476.2913。
Infer that the structure of target product is as follows through above data:
Embodiment 11
It is added in reaction tube 0.1 mM of di-t-butyl (the chloro- 1H- indoles -1- base of 5-) phosphine oxide, 0.01 mM three
(dibenzalacetone) two palladium, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 2- bromine
Pyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene stir anti-as solvent at 90 DEG C, revolving speed 700rpm
After answering 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase simultaneously
It is dried, filtered, is concentrated under reduced pressure using 0.5g anhydrous magnesium sulfate, then pass through column chromatographic isolation and purification, column chromatographic eluate used
Target product, yield 46% are obtained for the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 33, Figure 34 and Figure 35, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.49 (d, J=8.0Hz, 1H), 7.34 (s, 1H), 7.12 (d, J=
8.0Hz, 1H), 6.84 (d, J=2.0Hz, 1H), 1.35 (d, J=14.8Hz, 17H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.8,133.9,130.2 (d, J=4.1Hz), 128.7 (d, J=
4.5Hz), 126.3,121.5,111.2,106.6,106.2 (d, J=4.8Hz), 95.9,39.3 (d, J=66.6 Hz),
27.1,18.8,11.5;
31P NMR(162MHz,CDCl3)δ63.49-62.60(m);
IR(KBr)νmax 2939,2868,1459,1372,1235,1132,997,879,757,671,474cm-1;
HRMS(ESI)Calcd for C27H43ClNNaOPSi[M+Na]+:514.2432,Found 514.2435。
Infer that the structure of target product is as follows through above data:
Embodiment 12
It is added in reaction tube 0.1 mM of di-t-butyl (3- Methyl-1H-indole -1- base) phosphine oxide, 0.01 mmoles
That tris(dibenzylideneacetone) dipalladium, 0.20 mM of silver carbonate, 0.10 mM of trifluoromethayl sulfonic acid copper, 0.02 mM
3- chloropyridine, 0.18 mM of triisopropylsilyl alkynes bromine, 1.5 milliliters of toluene are stirred at 90 DEG C, revolving speed 700rpm as solvent
After mixing reaction 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic
It is dried, filtered mutually and using 0.5g anhydrous magnesium sulfate, is concentrated under reduced pressure, then by column chromatographic isolation and purification, column chromatography used is washed
The petroleum ether that de- liquid is volume ratio 30:1: ethyl acetate mixed solvent obtains target product, yield 84%.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 36, Figure 37 and Figure 38, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.57 (d, J=7.2Hz, 1H), 7.46 (d, J=7.6Hz, 1H), 7.12
(t, J=7.2Hz, 1H), 7.04 (s, 1H), 2.29 (s, 3H), 1.34 (d, J=14.8Hz, 18H), 1.16 (s, 21H);
13C NMR(100MHz,CDCl3) δ=138.9,133.5,132.3 (d, J=3.9Hz), 125.2 (d, J=
2.5Hz), 121.1,119.1,116.6 (d, J=5.2Hz), 112.4,107.6,94.6,39.1 (d, J=67.7 Hz),
27.1,18.8,11.5,9.7;
31P NMR(162MHz,CDCl3)δ61.79-61.08(m);
IR(KBr)νmax 2943,2869,1466,1390,1228,1128,1005,908,743,660,474cm-1;
HRMS(ESI)Calcd for C28H47NOPSi[M+H]+:472.3159,Found 472.3161。
Infer that the structure of target product is as follows through above data:
Embodiment 13
It is added in reaction tube 0.1 mM of di-t-butyl (1H- indoles -1- base) phosphine oxide, 0.01 mM of three (two Asia
Benzylacetone) two palladiums, 0.18 mM of silver carbonate, 0.15 mM of trifluoromethayl sulfonic acid copper, 0.02 mM of 3- chloropyridine,
0.18 mM of t-Butyldimethylsilyl alkynes bromine, 1.5 milliliters of toluene stir anti-as solvent at 90 DEG C, revolving speed 700rpm
After answering 12 hours, stops heating and stirring, be cooled to room temperature, 5mL water is added, is extracted with ethyl acetate 3 times, merge organic phase simultaneously
It is dried, filtered, is concentrated under reduced pressure using 0.5g anhydrous magnesium sulfate, then pass through column chromatographic isolation and purification, column chromatographic eluate used
Target product, yield 84% are obtained for the petroleum ether of volume ratio 30:1: ethyl acetate mixed solvent.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of gained target product are respectively as shown in Figure 39, Figure 40 and Figure 41, structural characterization
Data are as follows:
1H NMR(400MHz,CDCl3) δ=7.54 (d, J=7.6Hz, 1H), 7.30 (d, J=1.6Hz, 1H), 7.11
(t, J=7.6Hz, 1H), 6.69 (s, 1H), 1.35 (d, J=14.8Hz, 18H), 0.99 (s, 9H), 0.21 (s, 6H);
13C NMR(100MHz,CDCl3) δ=138.7,133.0,131.5 (d, J=4.0Hz), 128.2 (d, J=
4.8Hz), 121.6,121.3,112.1,108.1 (d, J=5.0Hz), 106.1,96.2,39.3 (d, J=67.3 Hz),
27.1,26.4,17.0,-4.5;
31P NMR(162MHz,CDCl3)δ62.80-61.92(m);
IR(KBr)νmax 2951,1686,1490,1399,1257,1124,988,818,739,661,598,525 cm-1;
HRMS(ESI)Calcd for C24H39NOPSi[M+H]+:416.2533,Found 416.2531。
Infer that the structure of target product is as follows through above data:
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of synthetic method of the 7- alkynyl Benzazole compounds of oxygen guiding, which is characterized in that comprise the following steps:
In the reactor, be added substrate di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound, alkynes halogen, palladium salt catalyst,
Oxidant, ligand and solvent are stirred to react at 80~100 DEG C, are cooled to room temperature after reaction, product through isolating and purifying,
Obtain the 7- alkynyl Benzazole compounds.
2. synthetic method according to claim 1, which is characterized in that the following institute of the chemical equation of synthesis process
Show:
In formula, R1Selected from hydrogen, 4- methyl, 4- methoxyl group, 4- Bian oxygroup, 4- fluorine, 4- chlorine, 4- bromine, 5- methyl, 5- methoxyl group, 5-
One or more of fluorine, 5- chlorine and 3- methyl;
R2For one of triisopropylsilyl, t-Butyldimethylsilyl;
X is chlorine, bromine or iodine.
3. synthetic method according to claim 1 or 2, which is characterized in that the palladium salt catalyst is palladium acetate, bis- (two
BENZYLIDENE ACETONE) one or more of palladium and tris(dibenzylideneacetone) dipalladium;The additional amount of the palladium salt catalyst
Molar ratio with di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound is 0.05~0.15:1.
4. synthetic method according to claim 1 or 2, which is characterized in that the additional amount and di-t-butyl of the alkynes halogen
The molar ratio of (1H- indoles -1- base) phosphine oxide-type compound is 1.6~2.6:1.
5. synthetic method according to claim 1 or 2, which is characterized in that the oxidant is the mixing of silver salt and mantoquita
Object is mixed to get by one or more of silver fluoride, silver carbonate, copper oxide, wolframic acid silver with trifluoromethayl sulfonic acid copper.
6. synthetic method according to claim 1 or 2, which is characterized in that the additional amount of silver salt and two in the oxidant
The molar ratio of tert-butyl (1H- indoles -1- base) phosphine oxide-type compound is 1.0~2.0:1, the addition of mantoquita in the oxidant
Amount and the molar ratio of di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound are 1.0~2.0:1.
7. synthetic method according to claim 1 or 2, which is characterized in that the ligand is 3- chloropyridine or 2- bromopyridine;
The additional amount of the ligand and the molar ratio of di-t-butyl (1H- indoles -1- base) phosphine oxide-type compound are 0.1~0.3:1.
8. synthetic method according to claim 1 or 2, which is characterized in that the solvent is toluene.
9. synthetic method according to claim 1 or 2, which is characterized in that the time being stirred to react is 6~20 small
When.
10. synthetic method according to claim 1 or 2, which is characterized in that the operation isolated and purified are as follows: will react
Liquid is extracted with ethyl acetate, and merges organic phase, is dried, filtered using anhydrous magnesium sulfate, remove organic solvent under reduced pressure, obtained and slightly produce
Object obtains the 7- alkynyl Benzazole compounds through column Chromatographic purification.
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