CN106278989A - The synthetic method of 3 cyanogen radical indole compounds - Google Patents

The synthetic method of 3 cyanogen radical indole compounds Download PDF

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CN106278989A
CN106278989A CN201610640475.6A CN201610640475A CN106278989A CN 106278989 A CN106278989 A CN 106278989A CN 201610640475 A CN201610640475 A CN 201610640475A CN 106278989 A CN106278989 A CN 106278989A
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phenyl
reaction
trifluoromethyl
reaction tube
giene
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CN106278989B (en
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范学森
张蓓蓓
张新迎
李彬
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Henan Normal University
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses the synthetic method of a kind of 3 cyanogen radical indole compounds, belong to technical field of organic synthesis.Technical scheme main points are: neighbour's bromine cyanobenzene or derivatives thereof, ammonia and aldehyde compound are dissolved in solvent, are subsequently adding catalyst, part or/and alkali, prepare 3 cyanogen radical indole compounds in 90 110 DEG C of reactions in the presence of the air.The present invention, from the raw material of simple easily preparation, by one pot of multicomponent cascade reaction, directly obtains 3 cyanogen radical indole compounds, and this building-up process is easy to operate, and reaction condition is gentle, and wide application range of substrates is suitable for industrialized production.

Description

The synthetic method of 3-cyanogen radical indole compounds
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the synthetic method of a kind of 3-cyanogen radical indole compounds.
Background technology
Research shows, many 3-cyanoindole derivants all have significant biological activity, are potential estrogen receptor Part, hepatitis C virus inhibitors and treating cardiovascular disease medicine.Additionally, 3-cyanogen radical indole compounds is still prepared many Plant the key intermediate of fine chemicals.In view of its importance, people successively develop and multiple construct 3-cyanoindole structure The effective ways of skeleton.According to the architectural feature of substrate used, existing synthetic method can be roughly divided into following three classes: 1) via 3-carbonyl, oximido, methylol, the functional group conversions of halogen substiuted indole synthesize；2) via the direct C (sp of indole 3-position2)- H bond activation and cyanalation synthesize；3) synthesize via the cyclization of non-Benzazole compounds.Although disclosed in these documents Synthesis strategy is all effective and reliable, but still suffers from some problem demanding prompt solutions.Wherein, first is usual with the third method Needing just can complete through multiple synthesis steps, the second synthesis strategy then generally requires use noble metal catalyst and poisonous Cyanogen source, and it is only applicable on nitrogen-atoms the indole derivatives with blocking group.These weak points make above-mentioned synthesis side Method application in actual production is very restricted.Therefore, study and develop and with commercially available cheap and safe reagent be Raw material, carry out on synthetic nitrogen atom the 3-cyanogen radical indole compounds without any substituted radical via easy operating procedure, no Only there is certain theory significance, and there is important using value.
Summary of the invention
Present invention solves the technical problem that the synthetic method that there is provided a kind of 3-cyanogen radical indole compounds, utilize this conjunction One-tenth method, by one pot of multicomponent cascade reaction, can directly obtain 3-cyanogen radical indole from the raw material of simple easily preparation Compound, this building-up process is easy to operate, and reaction condition is gentle, and wide application range of substrates is suitable for industrialized production.
The present invention solves that above-mentioned technical problem adopts the following technical scheme that, the synthesis side of 3-cyanogen radical indole compounds Method, it is characterised in that: neighbour's bromine cyanobenzene or derivatives thereof, ammonia and aldehyde compound are dissolved in solvent, be subsequently adding catalyst, Part and alkali, prepare 3-cyanogen radical indole compounds, the reaction in this synthetic method in 90-110 DEG C of reaction in the presence of the air Equation is:
Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group be unitary replace or Binary replaces, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, on this substituted-phenyl phenyl ring Substituent group is fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group be the para-position on phenyl ring, meta or Ortho position, solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, urges Agent is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, part be L-PROLINE, N, N '-dimethyl ethylenediamine, N, N, N ', N '-tetramethylethylenediamine or 1,10-phenanthroline, alkali is potassium carbonate, sodium carbonate, carbonic acid Caesium, tripotassium phosphate or potassium tert-butoxide.
The synthetic method of 3-cyanogen radical indole compounds of the present invention, it is characterised in that: by neighbour's bromine cyanobenzene or its spread out Biology, ammonia and aldehyde compound are dissolved in solvent, are subsequently adding catalyst and alkali, in the presence of the air in 90-110 DEG C of reaction Preparing 3-cyanogen radical indole compounds, the reaction equation in this synthetic method is:
Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group be unitary replace or Binary replaces, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, on this substituted-phenyl phenyl ring Substituent group is fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group be the para-position on phenyl ring, meta or Ortho position, solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, urges Agent is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, and alkali is potassium carbonate, carbonic acid Sodium, cesium carbonate, tripotassium phosphate or potassium tert-butoxide.
The synthetic method of 3-cyanogen radical indole compounds of the present invention, it is characterised in that: by neighbour's bromine cyanobenzene or its spread out Biology, ammonia and aldehyde compound are dissolved in solvent, are subsequently adding catalyst and part, anti-in 90-110 DEG C in the presence of the air Should prepare 3-cyanogen radical indole compounds, the reaction equation in this synthetic method is:
Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group be unitary replace or Binary replaces, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, on this substituted-phenyl phenyl ring Substituent group is fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group be the para-position on phenyl ring, meta or Ortho position, solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, urges Agent is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, part be L-PROLINE, N, N '-dimethyl ethylenediamine, N, N, N ', N '-tetramethylethylenediamine or 1,10-phenanthroline.
The present invention compared with prior art has the advantage that (1) building-up process is one pot of multicomponent cascade reaction, process Simply, efficiently, avoid at due to the use of plurality of reagents and the purification to each step reaction intermediate in multistep reaction simultaneously The wastings of resources that cause such as reason and environmental pollution；(2) raw material is cheap and easy to get or raw material is easily prepared；(3) reaction condition is gentle, Easy and simple to handle；(4) substrate is applied widely.Therefore, the present invention is that the synthesis of 3-cyanogen radical indole compounds provides one Economical and practical and the new method of environmental protection.
Detailed description of the invention
By the following examples the foregoing of the present invention is described in further details, but this should be interpreted as this The scope inventing above-mentioned theme is only limitted to below example, and all technology realized based on foregoing of the present invention belong to this Bright scope.
Embodiment 1
1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-phenyl-3-cyanoindole 4a (96.0mg, 88%).The sign data of this compound are as follows:1H NMR(400MHz, DMSO-d6) δ: 7.24-7.34 (m, 2H), 7.52-7.58 (m, 2H), 7.60-7.66 (m, 3H), 7.99 (d, J=7.6Hz, 2H),12.62(s,1H).13C NMR(100MHz,DMSO-d6)δ:81.3,112.6,117.0,118.4,122.0,123.9, 127.0,128.3,129.30,129.33,129.9,135.5,144.7.MS:m/z 219[M+H]+。
Embodiment 2
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) With strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (34.9mg, 32%).
Embodiment 3
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Cu-lyt. (0.05mmol, 4.9mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) With strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (17.5mg, 16%).
Embodiment 4
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), cuprous bromide (0.05mmol, 7.2mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) With strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (19.6mg, 18%).
Embodiment 5
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), copper chloride (0.05mmol, 8.5mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) and Strong aqua ammonia (3,26%, 0.5mL), seals reaction tube in the presence of the air, is subsequently placed in 100 DEG C of oil baths stirring reaction 20h, Obtain product 2-phenyl-3-cyanoindole 4a (16.4mg, 15%).
Embodiment 6
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), copper acetate (0.05mmol, 9.1mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) and Strong aqua ammonia (3,26%, 0.5mL), seals reaction tube in the presence of the air, is subsequently placed in 100 DEG C of oil baths stirring reaction 20h, Obtain product 2-phenyl-3-cyanoindole 4a (24.0mg, 22%).
Embodiment 7
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), copper trifluoromethanesulfcomposite (0.05mmol, 18.1mg), potassium carbonate (0.5mmol, 69.1mg), N,N-dimethylformamide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (3.3mg, 3%).
Embodiment 8
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), DMF (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, It is subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (81.8mg, 75%).
Embodiment 9
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), N, N '-dimethyl ethylenediamine (0.1mmol, 8.8mg), DMF (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air will be anti- Answer the seal of tube, be subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtain product 2-phenyl-3-cyanoindole 4a (49.1mg, 45%).
Embodiment 10
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), N, N, N ', N '-tetramethyl second two Amine (0.1mmol, 11.6mg), DMF (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air will Reaction tube seal, be subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtain product 2-phenyl-3-cyanoindole 4a (54.6mg, 51%).
Embodiment 11
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), 1,10-phenanthroline (0.1mmol, 18.0mg), DMF (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, It is subsequently placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (65.5mg, 60%).
Embodiment 12
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), N-Methyl pyrrolidone (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, so It is placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (22.9mg, 21%).Embodiment 13
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), isopropanol (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, is subsequently placed in In 100 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (21.8mg, 20%).
Embodiment 14
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), PEG400 (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then It is placed in 100 DEG C of oil baths stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (69.8mg, 64%).
Embodiment 15
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), sodium carbonate (0.5mmol, 53.0mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 100 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (70.9mg, 65%).
Embodiment 16
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), cesium carbonate (0.5mmol, 162.9mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 100 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (73.1mg, 67%).
Embodiment 17
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), tripotassium phosphate (0.5mmol, 106.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 100 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (67.7mg, 62%).
Embodiment 18
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium tert-butoxide (0.5mmol, 61.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 100 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (74.2mg, 68%).
Embodiment 19
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and dense Ammonia (3,26%, 0.5mL), seals reaction tube in the presence of the air, is subsequently placed in 100 DEG C of oil baths stirring reaction 20h, Product 2-phenyl-3-cyanoindole 4a (62.2mg, 57%).
Embodiment 20
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 110 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (88.4mg, 81%).
Embodiment 21
Method as described in embodiment 1, in 25mL reaction tube add 1a (0.5mmol, 98.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) and strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, then puts In 90 DEG C of oil baths, stirring reaction 20h, obtains product 2-phenyl-3-cyanoindole 4a (82.9mg, 76%).
Embodiment 22
1a (0.5mmol, 98.0mg), 2b (0.75mmol, 93.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-fluorophenyl)-3-cyanoindole 4b (99.2mg, 84%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.26 (t, J=7.2Hz, 1H), 7.32 (t, J=7.2Hz, 1H), 7.49 (t, J=8.8Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 8.02 (dd, J1=8.4Hz, J2=5.2Hz, 2H), 12.62(s,1H).13C NMR(100MHz,DMSO-d6)δ:81.4,112.6,116.4(d,2JC-F=22.5Hz), 116.9, 118.3,122.1,123.9,125.9(d,4JC-F=2.8Hz), 128.2,129.3 (d,3JC-F=8.7Hz), 135.5,143.8, 162.8(d,1JC-F=246.4Hz) .HRMS calcd for C15H10FN2:237.0823[M+H]+,found:237.0828。
Embodiment 23
1a (0.5mmol, 98.0mg), 2c (0.75mmol, 105.4mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-chlorphenyl)-3-cyanoindole 4c (105.3mg, 83%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.26 (t, J=7.2Hz, 1H), 7.30-7.34 (m, 1H), 7.56 (d, J=8.0Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 7.70 (d, J=8.4Hz, 2H), 7.98 (d, J=8.4Hz, 2H), 12.67 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:82.2,113.2,117.2,118.9,122.6,124.6,128.66,128.69,129.1, 129.9,135.1,136.0,143.8.MS:m/z 253[M+H]+。
Embodiment 24
1a (0.5mmol, 98.0mg), 2d (0.75mmol, 138.8mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-bromophenyl)-3-cyanoindole 4d (83.6mg, 56%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.28 (t, J=7.2Hz, 1H), 7.32-7.36 (m, 1H), 7.57 (d, J=8.4Hz, 1H), 7.64-7.67 (m, 1H), 7.86 (d, J=8.8Hz, 2H), 7.93 (d, J=8.4Hz, 2H), 12.70 (s, 1H).13C NMR (100MHz,DMSO-d6)δ:81.7,114.8,116.7,118.0,124.5,127.2,127.5,129.4,129.8,130.7, 134.5,146.6.MS:m/z 297[M+H]+。
Embodiment 25
1a (0.5mmol, 98.0mg), 2e (0.75mmol, 130.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-trifluoromethyl)-3-cyanoindole 4e (122.7mg, 85%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:7.29-7.32(m,1H),7.38(td,J1=7.6Hz, J2=1.2Hz, 1H), 7.61 (d, J =8.0Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 8.03 (d, J=8.4Hz, 2H), 8.20 (d, J=8.0Hz, 2H), 12.85 (s,1H).13C NMR(150MHz,DMSO-d6)δ:83.2,113.4,117.0,119.1,122.8,124.4(q,1JC-F= 270.45Hz),125.0,126.8(q,3JC-F=3.45Hz), 128.2,128.7,130.2 (q,2JC-F=31.95Hz), 133.7,136.2,143.1.MS:m/z 287[M+H]+。
Embodiment 26
1a (0.5mmol, 98.0mg), 2f (0.75mmol, 98.3mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-cyano-phenyl)-3-cyanoindole 4f (75mg, 62%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.29 (t, J=7.6Hz, 1H), 7.36 (t, J=7.6Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 8.10 (d, J=8.4Hz, 2H), 8.15 (d, J=8.8Hz, 2H), 12.83 (s, 1H) .13C NMR(100MHz,DMSO-d6)δ:83.0,111.9,112.9,116.5,118.4,118.7,122.4,124.7, 127.5,128.2,133.2,133.5,135.8,142.1.HRMS calcd for C16H10N3:244.0869[M+H]+, found:244.0868。
Embodiment 27
1a (0.5mmol, 98.0mg), 2g (0.75mmol, 90.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-tolyl)-3-cyanoindole 4g (94.1mg, 81%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6)δ:2.39(s,3H),7.22-7.28(m,1H),7.31(dd,J1=7.2Hz, J2=1.2Hz, 1H), 7.42 (d, J=8.0Hz, 2H), 7.54 (d, J=7.6Hz, 1H), 7.63 (d, J=7.6Hz, 1H), 7.88 (d, J=8.4Hz, 2H),12.54(s,1H).13C NMR(100MHz,DMSO-d6)δ:20.9,80.9,112.5,117.1,118.2,121.9, 123.7,126.6,126.8,128.3,129.8,135.4,139.8,144.9.MS:m/z 233[M+H]+。
Embodiment 28
1a (0.5mmol, 98.0mg), 2h (0.75mmol, 102.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-anisyl)-3-cyanoindole 4h (110.7mg, 89%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 3.85 (s, 3H), 7.19 (d, J=8.8Hz, 2H), 7.23 (t, J=8.0Hz, 1H), 7.26- (7.30 m, 1H), 7.52 (d, J=7.6Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.94 (d, J=9.2Hz, 2H), 12.47 (s,1H).13C NMR(100MHz,DMSO-d6)δ:55.4,80.2,112.4,114.8,117.3,118.1,121.7,121.8, 123.5,128.3,128.4,135.4,144.9,160.5.MS:m/z 249[M+H]+。
Embodiment 29
1a (0.5mmol, 98.0mg), 2i (0.75mmol, 90.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(3-tolyl)-3-cyanoindole 4i (92mg, 79%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 2.42 (s, 3H), 7.25 (t, J=7.2Hz, 1H), 7.31 (t, J=7.2Hz, 1H), 7.33- (7.36 m, 1H), 7.50 (t, J=8.0Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 7.78- 7.80(m,2H),12.58(s,1H).13C NMR(100MHz,DMSO-d6)δ:21.0,81.2,112.6,117.0,118.3, 122.0,123.8,124.1,127.4,128.3,129.2,129.3,130.6,135.5,138.6,144.8.MS:m/z 233 [M+H]+。
Embodiment 30
1a (0.5mmol, 98.0mg), 2j (0.75mmol, 90.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(2-tolyl)-3-cyanoindole 4j (96.8mg, 83%).The sign data of this compound are as follows:1H NMR (400MHz,CDCl3)δ:2.43(s,3H),7.29-7.36(m,4H),7.39(dd,J1=8.0Hz, J2=1.2Hz, 1H), 7.42-7.48(m,2H),7.76-7.78(m,1H),8.73(br s,1H).13C NMR(100MHz,CDCl3)δ:20.1, 86.8,111.7,116.4,119.5,122.4,124.2,126.3,128.0,129.2,130.2,131.1,134.8,137.0, 145.9.MS:m/z 233[M+H]+。
Embodiment 31
1a (0.5mmol, 98.0mg), 2k (0.75mmol, 117.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(1-naphthyl)-3-cyanoindole 4k (117mg, 87%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6)δ:7.29-7.38(m,2H),7.58-7.64(m,3H),7.69-7.73(m,2H),7.79-7.81 (m, 1H), 7.86-7.89 (m, 1H), 8.08-8.10 (m, 1H), 8.16 (d, J=8.4Hz, 1H), 12.71 (s, 1H).13C NMR (100MHz,DMSO-d6)δ:85.6,113.2,116.8,118.9,122.5,124.2,125.5,125.9,127.1,127.8, 127.9,128.1,129.1,129.4,130.8,131.2,133.8,136.0,145.4.MS:m/z 269[M+H]+。
Embodiment 32
1a (0.5mmol, 98.0mg), 2l (0.75mmol, 84.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(2-thienyl)-3-cyanoindole 4l (74mg, 66%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.25 (t, J=7.2Hz, 1H), 7.27-7.34 (m, 2H), 7.53 (d, J=8.4Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.85-7.86 (m, 2H), 12.65 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:80.7, 112.4,116.5,118.2,122.1,124.1,127.7,127.9,128.3,129.0,131.1,135.4,139.2.MS:m/ z 225[M+H]+。
Embodiment 33
1a (0.5mmol, 98.0mg), 2m (0.75mmol, 80.3mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-(4-pyridine radicals)-3-cyanoindole 4m (62.8mg, 57%).The sign data of this compound are as follows:1H NMR (400MHz,DMSO-d6) δ: 7.32 (t, J=7.2Hz, 1H), 7.40 (t, J=7.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.97 (dd, J1=8.4Hz, J2=1.2Hz, 2H), 8.84 (d, J=6.4Hz, 2H), 12.96(s,1H).13C NMR(100MHz,DMSO-d6)δ:83.3,113.0,116.3,118.7,120.5,122.4,124.8, 128.1,135.8,136.2,141.0,150.7.HRMS calcd for C14H10N3:220.0869[M+H]+,found: 220.0875。
Embodiment 34
1a (0.5mmol, 98.0mg), 2n (0.75mmol, 84.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-cyclohexyl-3-cyanoindole 4n (81.5mg, 72%).The sign data of this compound are as follows:1H NMR (400MHz,CDCl3)δ:1.25-1.35(m,1H),1.39-1.50(m,2H),1.56-1.66(m,2H),1.78-1.82(m, 1H),1.87-1.92(m,2H),2.06-2.10(m,2H),3.01-3.09(m,1H),7.22-7.26(m,2H),7.27-7.40 (m,1H),7.66-7.68(m,1H),8.64(br s,1H).13C NMR(100MHz,CDCl3)δ:25.7,26.2,32.4, 37.6,83.2,111.4,116.6,119.0,122.0,123.4,127.8,134.2,153.6.HRMS calcd for C15H16N2Na:247.1206[M+Na]+,found:247.1176。
Embodiment 35
1a (0.5mmol, 98.0mg), 2o (0.75mmol, 64.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-isobutyl group-3-cyanoindole 4o (74.3mg, 75%).The sign data of this compound are as follows:1H NMR (400MHz,CDCl3) δ: 1.00 (s, 3H), 1.02 (s, 3H), 2.09-2.20 (m, 1H), 2.82 (d, J=7.2Hz, 2H), 7.22-7.28(m,2H),7.39-7.42(m,1H),7.65-7.68(m,1H),8.83(br s,1H).13C NMR(100MHz, CDCl3)δ:22.4,29.3,36.6,85.5,111.5,116.7,119.0,122.0,123.4,127.6,134.6, 148.5.MS:m/z 199[M+H]+。
Embodiment 36
1a (0.5mmol, 98.0mg), 2p (0.75mmol, 100.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 2-phenethyl-3-cyanoindole 4p (107.9mg, 87%).The sign data of this compound are as follows:1H NMR (400MHz,CDCl3) δ: 3.09 (t, J=7.6Hz, 2H), 3.27 (t, J=7.6Hz, 2H), 7.17-7.19 (m, 2H), 7.21- 7.26(m,3H),7.27-7.32(m,3H),7.65-7.67(m,1H),8.36(br s,1H).13C NMR(100MHz,CDCl3) δ:29.4,35.2,85.3,111.4,116.1,119.1,122.1,123.5,126.8,127.5,128.4,128.8,134.5, 139.8,147.9.MS:m/z 247[M+H]+。
Embodiment 37
1b (0.5mmol, 132.0mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4q (112.3mg, 78%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:7.61(t,J =7.2Hz, 2H), 7.67 (t, J=7.6Hz, 2H), 7.75 (d, J=8.4Hz, 1H), 7.95 (s, 1H), 8.02 (d, J= 7.2Hz,2H),13.04(s,1H).13C NMR(100MHz,DMSO-d6)δ:82.3,113.6,115.7(q,3JC-F= 4.1Hz),116.0,120.3(q,3JC-F=4.0Hz), 122.7 (q,2JC-F=30.8Hz), 124.8 (q,1JC-F= 270.3Hz),127.1,127.6,128.7,129.3,130.4,137.1,146.9.MS:m/z 287[M+H]+。
Embodiment 38
1b (0.5mmol, 132.0mg), 2b (0.75mmol, 90.0mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4r (113.1mg, 74%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:7.52(t,J =8.8Hz, 2H), 7.60 (d, J=8.4Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.91 (s, 1H), 8.02-8.05 (m, 2H),13.02(s,1H).13C NMR(100MHz,DMSO-d6)δ:82.3,113.5,115.7(q,3JC-F=4.1Hz), 115.9,116.4(d,2JC-F=21.6Hz), 120.2 (q,3JC-F=3.9Hz), 122.7 (q,2JC-F=31.5Hz), 124.8 (q,1JC-F=269.4Hz), 125.2 (d,4JC-F=4.1Hz), 127.5,129.5 (d,3JC-F=8.6Hz), 137.0,145.8, 163.1(d,1JC-F=246.7Hz) .HRMS calcd for C16H9F4N2:305.0697[M+H]+,found:305.0689。
Embodiment 39
1b (0.5mmol, 132.0mg), 2h (0.75mmol, 102.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4s (129.7mg, 82%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:3.88(s, 3H), 7.22 (d, J=8.0Hz, 2H), 7.59 (d, J=8.8Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 7.91 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 12.89 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:55.4,81.2,113.3, 114.8,115.4(q,3JC-F=4.6Hz), 116.4,120.0 (q,3JC-F=3.1Hz), 121.0,122.6 (q,2JC-F= 31.4Hz),124.9(q,1JC-F=269.7Hz), 127.8,128.7,137.1,147.1,160.9.HRMS calcd for C17H12F3N2O:317.0896[M+H]+,found:317.0888。
Embodiment 40
1c (0.5mmol, 128.1mg), 2a (0.75mmol, 79.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4t (124.4mg, 89%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:3.84(s, 3H), 3.85 (s, 3H), 7.02 (s, 1H), 7.08 (s, 1H), 7.50 (t, J=7.6Hz, 1H), 7.60 (t, J=7.6Hz, 2H), 7.93 (d, J=7.2Hz, 2H), 12.31 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:55.66,55.72,81.2, 95.4,99.8,117.4,121.2,126.3,129.2,129.7,129.8,142.5,146.6,148.1.MS:m/z 279[M+ H]+。
Embodiment 41
1c (0.5mmol, 128.1mg), 2b (0.75mmol, 93.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4u (119.6mg, 80%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:3.84(s, 3H),3.85(s,3H),7.00(s,1H),7.08(s,1H),7.45-7.49(m,2H),7.94-7.98(m,2H),12.33(s, 1H).13C NMR(100MHz,DMSO-d6)δ:55.67,55.71,81.2,95.4,99.8,116.3(d,2JC-F=21.8Hz), 117.3,121.1,126.4(d,4JC-F=3.1Hz), 128.6 (d,3JC-F=9.2Hz), 129.8,141.5,146.7,148.1, 162.4(d,1JC-F=246.0Hz) .HRMS calcd for C17H14FN2O2:297.1034[M+H]+,found:297.1031。
Embodiment 42
1c (0.5mmol, 128.1mg), 2g (0.75mmol, 90.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4v (120.1mg, 82%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:2.39(s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.00 (s, 1H), 7.07 (s, 1H), 7.40 (d, J=8.0Hz, 2H), 7.82 (d, J =8.0Hz, 2H), 12.24 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:20.9,55.67,55.72,80.7,95.4, 99.8,117.5,121.2,126.2,127.0,129.7,129.8,139.0,142.7,146.6,147.9.HRMS calcd for C18H17N2O2:293.1285[M+H]+,found:293.1283。
Embodiment 43
1c (0.5mmol, 128.1mg), 2p (0.75mmol, 100.6mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4w (121.7mg, 79%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6)δ:3.05(t,J =7.2Hz, 2H), 3.14 (t, J=7.2Hz, 2H), 3.80 (s, 6H), 6.97 (s, 1H), 6.98 (s, 1H), 7.18-7.22 (m, 3H), 7.28 (t, J=7.2Hz, 2H), 11.85 (s, 1H).13C NMR(100MHz,DMSO-d6)δ:28.7,34.4,55.7, 82.4,95.7,100.0,116.7,119.8,126.2,128.1,128.4,128.8,140.0,146.1,146.6, 147.1.HRMS calcd for C19H19N2O2:307.1441[M+H]+,found:307.1438。
Embodiment 44
1b (0.5mmol, 132.0mg), 2q (0.75mmol, 54.1mg), Hydro-Giene (Water Science). is added in 25mL reaction tube (0.05mmol, 9.5mg), potassium carbonate (0.5mmol, 69.1mg), L-PROLINE (0.1mmol, 11.5mg), dimethyl sulfoxide (2mL) with strong aqua ammonia (3,26%, 0.5mL), in the presence of the air reaction tube is sealed, be subsequently placed in 100 DEG C of oil baths stirring Reaction 20h.Add 10mL shrend to go out reaction, be extracted with ethyl acetate (10mL × 3), afterwards organic phase washed with water and saturated aqueous common salt Washing successively, anhydrous sodium sulfate is dried.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid Body product 4x (84mg, 67%).The sign data of this compound are as follows:1H NMR(400MHz,DMSO-d6) δ: 1.04 (t, J= 7.2Hz, 3H), 1.82-1.91 (m, 2H), 2.98 (t, J=7.6Hz, 2H), 7.49 (s, 2H), 7.95 (s, 1H), 9.31 (br s,1H).13C NMR(150MHz,CDCl3)δ:13.6,22.4,29.5,85.8,112.0,115.6,116.6(q,3JC-F= 4.05Hz),120.3(q,3JC-F=4.5Hz), 124.6 (q,2JC-F=31.2Hz), 124.7 (q,1JC-F=270.0Hz), 127.2,136.2.151.2.MS:m/z 253[M+H]+。
Embodiment above describes the ultimate principle of the present invention, principal character and advantage, the technical staff of the industry should Understanding, the present invention is not restricted to the described embodiments, and the simply explanation present invention's described in above-described embodiment and description is former Reason, under the scope without departing from the principle of the invention, the present invention also has various changes and modifications, and these changes and improvements each fall within In the scope of protection of the invention.

Claims (3)

  1. The synthetic method of 1.3-cyanogen radical indole compounds, it is characterised in that: by neighbour's bromine cyanobenzene or derivatives thereof, ammonia and aldehydes Compound is dissolved in solvent, is subsequently adding catalyst, part and alkali, prepares 3-cyano group in 90-110 DEG C of reaction in the presence of the air Benzazole compounds, the reaction equation in this synthetic method is:
    Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group is that unitary replaces or binary takes Generation, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, the substituent group on this substituted-phenyl phenyl ring For fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group is the para-position on phenyl ring, meta or ortho position, Solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, and catalyst is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, part is L-PROLINE, N, N '-two Methyl ethylenediamine, N, N, N ', N '-tetramethylethylenediamine or 1,10-phenanthroline, alkali is potassium carbonate, sodium carbonate, cesium carbonate, phosphoric acid Tripotassium or potassium tert-butoxide.
  2. The synthetic method of 2.3-cyanogen radical indole compounds, it is characterised in that: by neighbour's bromine cyanobenzene or derivatives thereof, ammonia and aldehydes Compound is dissolved in solvent, is subsequently adding catalyst and alkali, prepares 3-cyanoindole in 90-110 DEG C of reaction in the presence of the air Compounds, the reaction equation in this synthetic method is:
    Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group is that unitary replaces or binary takes Generation, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, the substituent group on this substituted-phenyl phenyl ring For fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group is the para-position on phenyl ring, meta or ortho position, Solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, and catalyst is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, alkali is potassium carbonate, sodium carbonate, carbonic acid Caesium, tripotassium phosphate or potassium tert-butoxide.
  3. The synthetic method of 3.3-cyanogen radical indole compounds, it is characterised in that: by neighbour's bromine cyanobenzene or derivatives thereof, ammonia and aldehydes Compound is dissolved in solvent, is subsequently adding catalyst and part, prepares 3-cyano group Yin in 90-110 DEG C of reaction in the presence of the air Diindyl compounds, the reaction equation in this synthetic method is:
    Wherein R1For hydrogen, trifluoromethyl or methoxyl group, the replacement mode of this trifluoromethyl or methoxyl group is that unitary replaces or binary takes Generation, R2For alkyl, 1-naphthyl, 2-thienyl, 4-pyridine radicals, phenyl or substituted-phenyl, the substituent group on this substituted-phenyl phenyl ring For fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or cyano group, the position of substituent group is the para-position on phenyl ring, meta or ortho position, Solvent is DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, isopropanol or PEG400, and catalyst is Hydro-Giene (Water Science)., cuprous bromide, Cu-lyt., copper chloride, copper acetate or copper trifluoromethanesulfcomposite, part is L-PROLINE, N, N '-two Methyl ethylenediamine, N, N, N ', N '-tetramethylethylenediamine or 1,10-phenanthroline.
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