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 PDF

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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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synthetic method
indoles
butyl
phosphine oxide
base
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CN109867694B (en
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伍婉卿
方松佳
江焕峰
蒋光彬
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South China University of Technology SCUT
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    • 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 System
    • 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

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

A kind of synthetic method of the 7- alkynyl Benzazole compounds of oxygen guiding
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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