CN110204481A - A kind of polysubstituted nitrogenous heteroaromatic compound and the preparation method and application thereof - Google Patents

A kind of polysubstituted nitrogenous heteroaromatic compound and the preparation method and application thereof Download PDF

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CN110204481A
CN110204481A CN201810166022.3A CN201810166022A CN110204481A CN 110204481 A CN110204481 A CN 110204481A CN 201810166022 A CN201810166022 A CN 201810166022A CN 110204481 A CN110204481 A CN 110204481A
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CN110204481B (en
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张振华
李宗洋
逄森
霍童雨
丰硕
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China Agricultural University
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China Agricultural University
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • 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
    • C07D401/10—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 linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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    • C09K2211/1018—Heterocyclic compounds
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    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1059—Heterocyclic compounds characterised by ligands containing three nitrogen atoms as heteroatoms

Abstract

The present invention relates to a kind of preparation method of polysubstituted nitrogenous heteroaromatic compound, the polysubstituted nitrogenous heteroaromatic compound has the structure such as logical formula (I) or (II)；The method includes following specific steps: transition-metal catalyst, 2 being added into reaction vessel, 2 '-bipyridine ligands and solvent, raw material A and raw material B are added after mixing, the precursor of raw material C or raw material D or raw material D are sufficiently added after reaction at room temperature, under the conditions of -10 DEG C~150 DEG C sufficiently react to get.Method provided by the invention is under the action of transition-metal catalyst, to prepare nitrogenous heteroaromatic compound using one kettle way using alkenyl azide, isonitrile and acetylene compound as raw material.Reaction involved in the method for the present invention has extraordinary tolerance and universality to functional group, can be used for synthesizing all kinds of different polysubstituted aminopyridines and aminoisoquinoline class compound, and do not need stringent anhydrous and oxygen-free condition, operates very simple.

Description

A kind of polysubstituted nitrogenous heteroaromatic compound and the preparation method and application thereof
Technical field
The present invention relates to organic synthesis field more particularly to a kind of polysubstituted nitrogenous heteroaromatic compound and its preparation sides Method and application.
Background technique
Fluorescent molecule mark detection technique is a kind of efficiently quick detection means in biological detection and small molecule detection, It is real since the difference of the fluorescence emission wavelengths of every kind of marker may be implemented that different material, different loci is marked simultaneously Existing high-throughput detection, so the development in exploitation and synthetic method for more fluorescent tag molecules just seems especially heavy It wants.The advantage that aminopyridine has high fluorescence conversion rate (=0.6) and molecular structure simple, stable, by its structure into The modification of row functional group can be further improved light conversion ratio, and adjust its absorption and launch wavelength, to adapt to not isolabeling The needs of object.
In recent years, people for the structural molecule of polysubstituted aminopyridine parent nucleus Study of synthesis method also continuous It carries out.Synthetic method for such compound mainly include the following types: method one, from aminopyridine, first with tradition Electrophilic/necleophilic reaction pyridine ring is modified after, recycle coupling reaction amino is just modified (referring to Chemistry A European Journal 2017,23,1-8.)；Method two, using substituted pyridine oxide under the phosphorus catalyst of equivalent, Amination is carried out to No. 2 positions of pyridine, prepares pyridine amine (referring to Organic Letters 2010,12,5254-5257.)；Method Three, it is catalyzed using the malononitrile derivative of 1,3- dicarbapentaborane class compound, aromatic aldehyde, aromatic amine and severe toxicity at Fe (III) Lower multicomponent prepares pyridine amine (referring to The Journal of Organic Chemistry 2014,79,8882-8888.).
Following deficiency is primarily present for above mentioned several method: 1), needing repeatedly reaction, can not once construct pyrrole Pyridine amine, such as the above method one and method two；2), Atom economy is poor, needs the phosphorus catalyst using equivalent, is preparing product A large amount of by-product is generated simultaneously, such as method two；3) nitrile compounds for, needing to use severe toxicity, such as the above method three；4), Substrate universality is insufficient, obtained compound photoluminescent property is still insufficient (referring specifically to Heterocycles 2012,85, 2713-2721.).In today tightened up to environmental protection and protection of resources, high atom economy/step economy, original are developed The method of material high security is particularly important.
Summary of the invention
It is an object of the invention to overcome the deficiencies of existing technologies, a kind of polysubstituted nitrogenous heteroaromatic compound is provided Preparation method.Method provided by the invention has very extensive substrate adaptability, can synthesize difference by this method and take more The nitrogenous heteroaromatic compound in generation；And this method can disposably prepare target compound as one kettle way, entire reaction tool There is high atom economy, nitrogen is unique by-product of reaction.
Method provided by the invention is to be with raw material A (alkenyl azide), raw material B (isonitrile) and raw material C (acetylene compound) Raw material prepares nitrogenous heteroaromatic compound using one kettle way under the action of transition-metal catalyst.Target of the invention produces The polysubstituted nitrogenous heteroaromatic compound of object is preferably aminopyridines or aminoisoquinoline class compound.
Specifically, the present invention provides a kind of method for preparing polysubstituted nitrogenous heteroaromatic compound, it is described polysubstituted Nitrogenous heteroaromatic compound has the structure such as logical formula (I) or (II):
In the logical formula (I) or (II), R1~R6Be each independently selected from hydrogen atom, two substituted amidos, amide groups, ester group, Ketone carbonyl, siloxy, halogen, aryl, heteroaryl, naphthenic base, heterocycle, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkane Base, cycloalkyl-alkyl, heterocyclylalkyl group or aryl-alkoxy-alkyl；And the R1~R6In, at least two groups are not hydrogen original Son；
The reaction mechanism mechanism of reaction of the method are as follows:
Or
It comprises the following specific steps that: transition-metal catalyst, 2,2 '-bipyridine ligands being added into reaction vessel and have Raw material A and raw material B is added in solvent after mixing, sufficiently adds raw material C or raw material D or raw material D after reaction at room temperature Precursor, under the conditions of -10 DEG C~150 DEG C sufficiently react to get.The reaction only need to ensure that each raw material sufficiently reacts； It, can be by raw material A, the control of the molar ratio of the precursor of raw material B and raw material C/ raw material D/ raw material D 1 in actual fabrication process: 1.0:1.2 in the range of~1:1.2:2.0.
Aryl of the present invention can be substituted or unsubstituted aryl.It can replace with one or more on the aryl The position of substituent group is not particularly limited in base, ortho position, meta position, contraposition；The substituent group does not limit in any way, Common substituent group such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde radical, ketone carbonyl and halogen Element etc.；When with multi-substituent, this multiple substituent group can be identical or different, and adjacent or similar two substituent groups can phase Mutually independent or cyclization.Aryl of the present invention is preferably monocycle or bicyclic aryl, the aryl of more preferably 6-14 carbon atom, Such as phenyl or naphthyl.Substituent group on the aryl is preferably alkyl, alkoxy, nitro, cyano, ester group, aldehyde radical, ketone carbonyl Base and halogen atom, more preferable halogenated alkyl, such as trifluoromethyl.
Heteroaryl of the present invention can be the substituted or unsubstituted aryl at least one nitrogen, oxygen or sulphur；It is described The position of substituent group can be not particularly limited with one or more substituent groups on heteroaryl, ortho position, meta position, contraposition； The substituent group does not limit in any way, common substituent group such as alkyl, alkoxy, siloxy, two substituted amidos, nitre Base, cyano, ester group, aldehyde radical, ketone carbonyl and halogen etc.；When with multi-substituent, this multiple substituent group can be identical or different, Adjacent or similar two substituent groups can mutually indepedent or cyclization.Hetero atom in heteroaryl of the present invention can be one A, two, three or four.The heteroaryl preferably comprises 5-30 atom, more preferable 6-20 atom, for example, thiophene, It is furans, pyrroles, pyrazoles, imidazoles, oxazole, thiazole, isoxazole, isothiazole, oxazoline, thiazoline, pyridine, pyrans, thiapyran, phonetic Pyridine, pyridazine, pyrazine, piperazine, azatropylidene, oxa- Zhuo, thiotropilium, indoles, benzimidazole, benzothiophene, benzofuran, benzo thiophene Azoles, benzoxazoles, benzo isoxazole, phenylpropyl alcohol isothiazole, quinoline, isoquinolin, quinazoline, carbazole, pteridine, purine, aza-phenanthrenes, a word used for translation Pyridine, azophenlyene, phenthazine etc..Substituent group on the heteroaryl is preferably alkyl, alkoxy, nitro, cyano, ester group, aldehyde radical, ketone Carbonyl or halogen atom, more preferable halogenated alkyl, such as trifluoromethyl.
Naphthenic base of the present invention can be substituted or unsubstituted naphthenic base；One or more can be had in the naphthenic base The position of substituent group is not particularly limited in a substituent group, ortho position, meta position, contraposition；The substituent group is not in any way It limits, common substituent group such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde radical, ketone carbonyl With halogen atom etc.；When with multi-substituent, this multiple substituent group can be identical or different, adjacent or similar two substituent groups It can mutually indepedent or cyclization.Naphthenic base of the present invention is preferably saturated or unsaturated monocycle or polycyclic carbocylic radical group, The naphthenic base preferably comprises 3-20 atom, more preferable 3-10 atom, such as cyclohexyl.
Heterocycle of the present invention can be substituted or unsubstituted heterocycle；One or more can be had on the heterocycle The position of substituent group is not particularly limited in a substituent group, ortho position, meta position, contraposition；The substituent group is not in any way It limits, common substituent group such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde radical, ketone carbonyl With halogen atom etc.；When with multi-substituent, this multiple substituent group can be identical or different, adjacent or similar two substituent groups It can mutually indepedent or cyclization.Preferably there are heterocycle of the present invention 1-4 to be selected from the heteroatomic saturation of N, S, O or insatiable hunger The monocycle or polycyclic heterocyclic group of sum, hetero atom therein can be one, two, three or four.The heterocycle is preferred Containing 5-30 atom, more preferable 6-20 atom, such as Azacyclyl, nitrogen, oxa- ring group, representative heterocycle include: Nafoxidine base, tetrahydro pyridyl, piperazinyl, morpholinyl etc..
Alkyl of the present invention can be substituted or unsubstituted level-one, second level or three-level alkyl；The substituent group not with Any mode limits, common substituent group such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde Base, ketone carbonyl and halogen atom etc.；When with multi-substituent, this multiple substituent group can be identical or different, adjacent or similar Two substituent groups can mutually indepedent or cyclization.Alkyl of the present invention is preferably the linear chain or branched chain for having 1~10 carbon atom Alkyl；Substituent group on the alkyl is preferably that alkoxy, siloxy, nitro, cyano, ester group, aldehyde radical, ketone carbonyl or halogen are former Son, more preferably halogen atom, such as fluorine, chlorine, bromine.Alkyl of the present invention be specifically as follows methyl, ethyl, propyl, isopropyl, Butyl, isobutyl group, tert-butyl, sec-butyl, amyl, neopentyl or halogenated C1-10Alkyl.As a preferred embodiment, the alkyl It can be trifluoromethyl.
Alkoxy of the present invention be preferably there is the straight or branched alkoxyl of 1~10 carbon atom, such as methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.
Alkenyl of the present invention can be substituted or unsubstituted alkenyl, not special to the position and quantity of substituent group Limitation, one, two, three, cis and trans.The substituent group does not limit in any way, common substitution Base such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde radical, ketone carbonyl and halogen atom etc.；Work as tool When having multi-substituent, this multiple substituent group can be identical or different, adjacent or similar two substituent groups can it is mutually indepedent or Cyclization.Alkenyl of the present invention is preferably the linear chain or branched chain alkenyl for having 2-10 carbon atom, and the substituent group on the alkenyl is excellent It is selected as alkoxy, siloxy, nitro, cyano, ester group, aldehyde radical, ketone carbonyl or halogen atom, more preferably halogen atom, such as fluorine, Chlorine, bromine.Alkenyl of the present invention is specifically as follows vinyl, acrylic, cyclobutenyl, isobutenyl, pentenyl, hexenyl or halogen For C2-10Alkenyl.
Alkynyl of the present invention can be substituted or unsubstituted alkynyl；The substituent group does not limit in any way, often The substituent group seen such as alkyl, alkoxy, siloxy, two substituted amidos, nitro, cyano, ester group, aldehyde radical, ketone carbonyl and halogen is former Son etc.；When with multi-substituent, this multiple substituent group can be identical or different, and adjacent or similar two substituent groups can phase Mutually independent or cyclization.Alkynyl of the present invention is preferably the linear chain or branched chain alkynyl with 2-10 carbon atom；On the alkynyl Substituent group be preferably alkoxy, siloxy, nitro, cyano, ester group, aldehyde radical, ketone carbonyl or halogen atom, more preferable halogen atom, Such as fluorine, chlorine, bromine.Alkynyl of the present invention be specifically as follows acetenyl, propinyl, butynyl, pentynyl, isoamyl alkynyl, oneself Alkynyl or halogenated C2-10Alkynyl.
The substituent group of two substituted amido of the present invention can be identical or different, is independently from each other alkyl or aryl, Such as N, N- dimethyl amido, N, N- diphenyl amido, N- Methyl-N-phenyl amido etc..
Amide groups of the present invention is-NH-CO-R4, wherein R4For H, C1-10Alkyl, aryl, such as acetamido, propionyl Amido and amide-based small etc..
Ester group of the present invention is-COO-R5, wherein R5For H, C1-10Alkyl, aryl, such as R5It can be methyl, second class, third Base, butyl；Formic acid ester group, acetate groups, propionic acid ester group and butyric acid ester group etc..
Ketone carbonyl of the present invention is-CO-R6, wherein R6For H, C1-10Alkyl, aryl, such as first carbonyl, B carbonyl, third Carbonyl and fourth carbonyl etc..
Siloxy of the present invention is-O-Si (R7)3, wherein R7It is identical or different, alone be selected from H, C1-10Alkyl, example Such as trimethicone, dimethyl ethyl siloxanes, dimethyl butyrate radical siloxane.
Halogen atom of the present invention refers to fluorine, chlorine, bromine or iodine atom etc..
In preparation method provided by the invention, in addition to reaction substrate, catalyst and solvent have also been used.Wherein:
The palladium catalyst useful commercial reagent, can be palladium, palladium salt, palladium with containing Phosphine ligands, containing n-donor ligand, oxygen-containing match (carrier can be titanium dioxide, siliceous material to the complex or supported palladium of the ligands such as body, sulfur-containing ligand or alkenyl ligand composition Material, barium sulfate, calcium carbonate, high molecular material etc.), it is preferably but not limited to one of following collection: palladium carbon, palladium oxide, hydrogen-oxygen Change palladium, palladium/titanium dioxide, Pd/Ph-SBA-15, Pd-BTP/SiO2, material load Pd, SiO2Load Pd, Lindla catalysis Agent, Pd/BaSO4, Pd/CaCO3, high molecular material load Pd.Its catalytic amount is preferably being based on the formula (II) compound In the range of 0.001-5% equivalent, more preferably in the range of 0.01-2.5% equivalent, the further preferably model of 0.05-0.1% equivalent In enclosing.
The rhodium catalyst useful commercial reagent can be rhodium, rhodium salt, rhodium and phosphorus-containing ligand, containing n-donor ligand, oxygen-containing match (carrier can be titanium dioxide to the complex or load rhodium of the ligands such as body, phosphorus-containing ligand, sulfur-containing ligand or alkenyl ligand composition Titanium, material, barium sulfate, calcium carbonate, high molecular material etc.).It is preferably but not limited to one of following collection: rhodium carbon, three Phenylphosphine radium chloride, { Rh (COD) Cl }2,{Rh(COD)OH}2,Rh(COD)(acac),{Rh(NBD)Cl}2.Its catalytic amount is excellent It is selected in the range of the 0.001-5% equivalent based on the formula (II) compound, the range more preferably in 0.01-2.5% equivalent It is interior, further preferably in the range of 0.05-0.1% equivalent.
The solvent is organic solvent, is preferably but not limited to one of following collection or several mixture: water, Methylene chloride, 1,2- dichloroethanes, chloroform, ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl n-butyl ether, methanol, ethyl alcohol, Isopropanol, benzene, toluene, acetonitrile, nitromethane, pentane, hexane etc..These solvent commercial reagents are not necessarily to special place Reason.
In preparation method provided by the invention, reaction temperature and reaction time are slightly different according to different raw materials, reaction Temperature is usually -10 DEG C to 150 DEG C, and preferably 120 DEG C to 130 DEG C, the reaction time is generally at 2-24 hours.If desired it heats, it can Using oil bath (such as silicone oil, paraffin oil etc.) or other heating methods.
The product of high-purity in order to obtain, the method for the invention can also include concentration step.Preferably, the concentration The methods of air-distillation, vacuum distillation can be used in process.After concentration, it can also include to product purifying.The purifying It is preferred that obtaining pure product using modes such as column chromatography, vacuum distillation and/or recrystallizations.As a preferred embodiment, described Purifying is the product for being evaporated under reduced pressure or being recrystallized to give again after column chromatographs after purification.
The method of the invention realizes from alkenyl azide compound, directly use isonitrile and alkynes/aryne precursor for original Material, one kettle way obtain corresponding polysubstituted nitrogenous heteroaromatic compound (i.e. polysubstituted aminopyridine or aminoisoquinoline class Close object), reaction efficiency is high, and reaction cost is low, and substrate universality is high.
The reaction as involved in method provided by the invention has extraordinary tolerance and universality to functional group, this A kind of completely new polysubstituted nitrogenous heteroaromatic compound is invented while providing, this compound can use provided by the invention Scheme is simply, efficiently prepared.
Specifically, the present invention provides a kind of polysubstituted nitrogenous heteroaromatic compound, have such as logical formula (I) or (II) Structure:
In the logical formula (I) or (II), R2And R6It is hydrogen atom, R1、R3、R4、R5It is each independently selected from ester group, virtue Base, heteroaryl, naphthenic base, heterocycle, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocycle Alkyl or aryl-alkoxy-alkyl.
The preferably described R of the present invention3、R4It is ester group.
The preferred R of the present invention1Selected from aryl, heteroaryl, naphthenic base, heterocycle, aryl alkyl, heteroaryl alkyl, naphthenic base Alkyl, heterocyclylalkyl group or aryl-alkoxy-alkyl.
The preferably described R of the present invention5It is (such as right selected from alkyl, naphthenic base, unsubstituted aryl (such as phenyl) or the aryl of substitution Methoxyphenyl).
As a preferred solution of the present invention, the polysubstituted nitrogenous heteroaromatic compound in following compound one Kind is a variety of:
The compound that method provided by the invention is prepared has fluorescent characteristic, can be applied to prepare fluorescent marker, It is preferred for the fluorescent marker that preparation is directed to large biological molecule.
Compared with prior art, reaction environment according to the present invention is more friendly, and reaction is in itself or it is in raw material Synthesis process conditional is mild, and Atom economy is high, reacts from alkenyl azide, one kettle way obtains accordingly to substituted-amino Pyridine/aminoisoquinoline class compound.Reaction involved in the method for the present invention has extraordinary tolerance and general to functional group Adaptive can be aryl, heteroaryl, naphthenic base, heterocycle, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, cycloalkanes Base alkyl, heterocyclylalkyl group, aryl-alkoxy-alkyl, substituent group can be alkyl, alkoxy, siloxy, two substituted amidos, Nitro, cyano, ester group, aldehyde radical, ketone carbonyl and halogen atom (F, Cl, Br, I) etc. can be used for synthesizing all kinds of different polysubstituted Aminopyridine and aminoisoquinoline class compound.Reaction according to the present invention does not need stringent anhydrous and oxygen-free condition, operation It is very simple.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1
A kind of novel compounds 2- spy fourth amino -6- phenylpyridine -3,4- dicarboxylic acid ethyl ester is present embodiments provided, point Minor are as follows: C21H26N2O4, structural formula are as follows:
The compound synthesizes to obtain using following specific steps:
Sequentially added into 5ml reaction tube { Rh (COD) Cl } 2 (2mg, 0.0038mmol) and 2,2 '-bipyridyls (1mg, 0.0075mmol), Isosorbide-5-Nitrae-dioxane (2ml) after stirring 5min, reuses syringe and (1- nitrine ethylene) base benzene is added (22mg, 0.15mmol), tert-butyl isonitrile (13mg, 17uL, 0.2mmol), reacts 5h at room temperature.After complete reaction, add Enter and butine diethyl phthalate (51mg, 48uL, 0.3mmol) is added with syringe, be heated to reacting 5h at 120 DEG C, TLC detection is complete After reaction.Solvent is concentrated under reduced pressure in system, and residue isolates and purifies (petroleum ether: ethyl acetate=50:1) by flash column chromatography, Obtain greenish yellow solid 40mg, yield 71%.
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ8.08–8.03(m,2H),7.97(s,1H),7.50–7.42(m,3H),6.98 (s, 1H), 4.36 (q, J=7.2Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 1.57 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.34 (t, J=7.2Hz, 3H)
13C NMR(101MHz,cdcl3)δ169.05,167.06,159.24,157.85,145.95,138.51, 130.00,128.76,127.36,105.81,101.13,61.82,61.42,51.85,29.31,14.27,14.14.
IR(neat)2920.62,1737.53,1687.46,1558.94,1370.21,1290.03,1186.35, 1128.80.
HRMS(ESI+)calcd for C21H27N2O4:371.1971,found:371.1959.
The method provided using above-described embodiment 1, is only adjusted correspondingly the substituent group of raw material, can be obtained as follows 2~22 compound represented of embodiment.
Embodiment 2
Novel compounds C is prepared according to 1 the method for embodiment22H28N2O4, products collection efficiency 60%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ7.99–7.91(m,3H),7.32–7.21(m,2H),6.94(s,1H),4.42– 4.23(m,4H),2.41(s,3H),1.56(s,9H),1.42–1.30(m,6H).
13C NMR(101MHz,cdcl3)δ169.17,167.10,159.30,157.88,145.90,140.25, 135.79,129.51,127.32,105.53,100.73,61.80,61.36,51.82,29.32,21.52,14.27,14.16.
IR(neat)2954.64,1737.67,1686.74,1558.48,1369.89,1289.68,1182.11, 1044.46.
HRMS(ESI+)calcd for C22H29N2O4:385.2127,found:385.2108.
Embodiment 3
Novel compounds C is prepared according to 1 the method for embodiment22H28N2O4, products collection efficiency 68%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.89–7.83(m,2H),7.39–7.33(m,1H),7.25 (d, J=6.4Hz, 1H), 6.96 (s, 1H), 4.36 (q, J=7.2Hz, 2H), 4.30 (q, J=7.2Hz, 2H), 2.43 (s, 3H), 1.56 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.34 (t, 3H)
13C NMR(75MHz,CDCl3)δ169.12,167.09,159.45,157.85,145.89,138.52,138.28, 130.77,128.68,128.05,124.59,105.88,101.00,61.80,61.39,51.82,29.31,21.74, 14.26,14.13.
IR(neat)2917.53,1737.76,1686.83,1559.92,1369.89,1255.88,1229.12, 1178.37.
HRMS(ESI+)calcd for C22H29N2O4:385.2127,found:385.2112.
Embodiment 4
Novel compounds C is prepared according to 1 the method for embodiment22H28N2O4, products collection efficiency 52%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.43–7.40(m,1H),7.31–7.28(m,1H),7.27– 7.24(m,2H),6.58(s,1H),4.37–4.27(m,4H),2.41(s,3H),1.47(s,9H),1.39–1.31(m,6H).
13C NMR(101MHz,cdcl3)δ168.89,167.20,162.79,157.71,145.06,140.33, 135.82,130.79,129.57,128.63,125.80,109.94,100.71,61.81,61.48,51.87,29.46, 20.72,14.26,14.14.
IR(neat)2929.90,1738.12,1688.51,1587.00,1460.82,1370.40,1286.77, 1135.14.
HRMS(ESI+)calcd for C22H29N2O4:385.2127,found:385.2114.
Embodiment 5
Novel compounds C is prepared according to 1 the method for embodiment22H25F3N2O4, products collection efficiency 52%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.14 (d, J=8.6Hz, 2H), 7.96 (s, 1H), 7.72 (d, J=8.6Hz, 2H), 6.99 (s, 1H), 4.37 (dd, J=14.4,7.2Hz, 2H), 4.31 (dd, J=7.1Hz, 2H), 1.56 (s, 9H), 1.39 (t, J=7.2Hz, 3H), 1.35 (t, J=7.1Hz, 3H)
13C NMR(101MHz,cdcl3)δ168.71,166.70,158.17,158.12,146.12,141.68,131.67 (q, J=32.5Hz), 127.65,125.68 (q, J=3.8Hz), 124.21 (q, J=544.5,272.2Hz), 106.43, 101.87,62.02,61.61,41.11,31.64,20.46,14.27,14.14,14.07.
IR(neat)2929.90,1737.52,1690.32,1585.18,1561.09,1463.92,1325.29, 1128.62.
HRMS(ESI+)calcd for C22H26F3N2O4:489.1845,found:489.1824.
Embodiment 6
Novel compounds C is prepared according to 1 the method for embodiment22H25FN2O4, products collection efficiency 58%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,cdcl3)δ8.06–8.01(m,2H),7.99(s,1H),7.17–7.11(m,2H),6.91 (s,1H),4.39–4.26(m,4H),1.55(s,9H),1.41–1.31(m,6H).
13C NMR (75MHz, DMSO) δ 168.92,167.02,164.16 (d, J=249.9Hz), 158.18,157.84, (146.09,134.73,129.28 d, J=8.5Hz), 115.73 (d, J=21.7Hz), 105.51,101.30,61.83, 61.45,51.86,29.30,14.25,14.12.
IR(neat)2979.38,1738.76,1687.27,1560.07,1508.00,1370.21,1289.91, 1256.39.
HRMS(ESI+)calcd for C21H26FN2O4:389.1877,found:389.1869.
Embodiment 7
Novel compounds C is prepared according to 1 the method for embodiment22H25ClN2O4, products collection efficiency 60%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,cdcl3)δ8.01–7.95(m,3H),7.46–7.40(m,2H),6.93(s,1H),4.36 (q, J=7.2Hz, 2H), 4.30 (q, J=7.2Hz, 2H), 1.55 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.34 (t, J= 7.2Hz,3H).
13C NMR(75MHz,CDCl3)δ168.83,166.98,158.02,157.82,146.10,137.05,136.14, 129.00,128.64,105.65,101.71,61.87,61.50,51.89,29.29,14.25,14.12.
IR(neat)2954.64,1736.96,1687.68,1590.99,1556.50,1370.06,1255.51, 1129.11.
HRMS(ESI+)calcd for C21H26ClN2O4:405.1581,found:405.1555.
Embodiment 8
Novel compounds C is prepared according to 1 the method for embodiment22H25BrN2O4, products collection efficiency 53%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.93–7.89(m,2H),7.61–7.57(m,2H),6.93 (s, 1H), 4.36 (q, J=7.3Hz, 2H), 4.30 (q, J=7.3Hz, 2H), 1.55 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.34 (t, J=7.1Hz, 3H)
13C NMR(75MHz,CDCl3)δ168.82,166.98,158.09,157.82,146.11,137.52,131.98, 128.91,124.56,105.63,101.79,61.88,61.51,51.90,29.29,14.26,14.12.
IR(neat)2923.71,1738.42,1689.52,1591.05,1371.13,1292.35,1185.15, 1129.17.
HRMS(ESI+)calcd for C21H26BrN2O4:449.1076,found:449.1051.
Embodiment 9
Novel compounds C is prepared according to 1 the method for embodiment22H28N2O5, products collection efficiency 58%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.02 (d, J=9.0Hz, 2H), 7.99 (s, 1H), 6.98 (d, J=9.0Hz, 2H), 6.91 (s, 1H), 4.35 (q, J=7.2Hz, 2H), 4.29 (q, J=7.1Hz, 2H), 3.87 (s, 3H), 1.56 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.33 (t, J=7.1Hz, 3H)
13C NMR(101MHz,cdcl3)δ169.22,167.11,161.34,158.90,157.89,145.92, 131.13,128.87,114.13,105.07,100.25,61.76,61.30,55.50,51.78,29.33,14.27,14.16.
IR(neat)2948.45,1736.53,1685.63,1589.89,1555.73,1509.79,1257.86, 1136.07.
HRMS(ESI+)calcd for C22H29N2O5:401.2076,found:401.2064.
Embodiment 10
Novel compounds C is prepared according to 1 the method for embodiment23H30N2O6, products collection efficiency 64%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 7.95 (s, 1H), 7.24 (d, J=2.3Hz, 2H), 6.94 (s, 1H), 6.55 (t, J=2.3Hz, 1H), 4.36 (q, J=7.2Hz, 2H), 4.30 (q, J=7.2Hz, 2H), 4.29-4.29 (m, 1H), 3.86 (s, 6H), 1.56 (s, 9H), 1.38 (t, J=7.2Hz, 3H), 1.34 (t, J=7.2Hz, 3H)
13C NMR(101MHz,cdcl3)δ169.03,166.98,161.04,158.73,157.65,145.93, 140.50,105.89,105.31,102.38,101.38,61.87,61.46,55.57,51.81,29.25,14.26,14.14.
IR(neat)2951.55,1751.55,1687.20,1560.80,1457.73,1231.50,1290.96, 1177.70.
HRMS(ESI+)calcd for C23H31N2O6:431.2182,found:431.2173.
Embodiment 11
Novel compounds C is prepared according to 1 the method for embodiment21H26N2O4, products collection efficiency 80%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,cdcl3)δ8.11–8.02(m,2H),7.90(s,1H),7.50–7.38(m,3H),6.97 (s,1H),4.41–4.26(m,4H),3.68–3.59(m,2H),1.73–1.63(m,2H),1.51–1.42(m,2H),1.42– 1.30 (m, 6H), 0.98 (t, J=7.3Hz, 3H)
13C NMR(101MHz,cdcl3)δ169.02,166.85,159.85,158.18,145.93,138.35, 130.11,128.71,127.37,106.14,100.74,61.85,61.39,41.03,31.71,20.46,14.26,14.15, 14.08.
IR(neat)2957.73,1736.78,1686,45,1559.53,1251.02,1192.48,1128.46, 1021.65.
HRMS(ESI+)calcd for C21H27N2O4:371.1971,found:371.1962.
Embodiment 12
Novel compounds C is prepared according to 1 the method for embodiment22H28N2O4, products collection efficiency 66%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 7.87 (s, 1H), 7.45 (d, J=7.8Hz, 1H), 7.31-7.23 (m, 3H), 6.63 (s, 1H), 4.39-4.28 (m, 4H), 3.54 (dd, J=12.4,7.0Hz, 2H), 2.46 (s, 3H), 1.65-1.57 (m, 2H), 1.46-1.32 (m, 8H), 0.94 (t, J=7.3Hz, 3H)
13C NMR(101MHz,cdcl3)δ168.86,166.94,163.56,157.83,145.31,139.60, 136.51,131.17,129.57,128.92,125.93,109.98,100.21,61.84,61.43,41.04,31.87, 20.94,20.41,14.26,14.15,14.04.
IR(neat)2957.73,1736.64,1687.33,1559.94,1368.04,1286.50,1187.17, 1130.33.
HRMS(ESI+)calcd for C22H29N2O4:385.2127,found:385.2121.
Embodiment 13
Novel compounds C is prepared according to 1 the method for embodiment22H25F3N2O4, products collection efficiency 57%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.16 (d, J=8.2Hz, 2H), 7.90 (s, 1H), 7.71 (d, J=8.1Hz, 2H), 6.99 (s, 1H), 4.42-4.29 (m, 4H), 3.63 (q, J=6.7Hz, 2H), 1.72-1.63 (m, 2H), 1.52-1.43 (m, 2H), 1.43-1.32 (m, 6H), 0.98 (t, J=7.3Hz, 3H)
13C NMR(101MHz,cdcl3)δ168.71,166.70,158.17,158.12,146.12,141.68,131.67 (q, J=32.5Hz), 127.65,125.68 (q, J=3.8Hz), 124.21 (q, J=544.5,272.2Hz), 106.43, 101.87,62.02,61.61,41.11,31.64,20.46,14.27,14.14,14.07.
IR(neat)2954.64,1739.18,1683.51,1560.95,1324.27,1292.98,1252.08, 1107.90.
HRMS(ESI+)calcd for C22H26F3N2O4:439.1845,found:439.1826.
Embodiment 14
Novel compounds C is prepared according to 1 the method for embodiment21H25ClN2O4, products collection efficiency 52%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,cdcl3)δ8.04–7.97(m,2H),7.90(s,1H),7.45–7.40(m,2H),6.92 (s, 1H), 4.40-4.28 (m, 4H), 3.62 (dd, J=12.4,7.0Hz, 2H), 1.71-1.62 (m, 2H), 1.50-1.42 (m, 2H), 1.39 (t, J=7.2Hz, 3H), 1.34 (t, J=7.1Hz, 3H), 0.98 (t, J=7.3Hz, 3H)
13C NMR(101MHz,cdcl3)δ168.87,166.76,158.55,158.13,146.06,136.79, 136.24,128.94,128.66,105.88,101.10,61.94,61.49,41.06,31.66,20.47,14.27,14.15, 14.08.
IR(neat)2967.01,1736.46,1687.40,1558.29,1374.23,1279.48,1250.32, 1129.89.
HRMS(ESI+)calcd for C21H26ClN2O4:405.1581,found:405.1563.
Embodiment 15
Novel compounds C is prepared according to 1 the method for embodiment23H28N2O4, products collection efficiency 65%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.08-8.00 (m, 2H), 7.89 (d, J=7.3Hz, 1H), 7.50-7.41 (m, 3H), 6.95 (s, 1H), 4.37 (q, J=7.2Hz, 2H), 4.31 (q, J=7.2Hz, 2H), 2.13-2.03 (m, 2H), 1.82- 1.73(m,2H),1.69–1.59(m,1H),1.52–1.45(m,2H),1.44–1.21(m,10H).
13C NMR(101MHz,cdcl3)δ169.07,166.81,159.84,157.44,146.05,138.38, 130.08,128.73,127.33,105.98,100.48,61.84,61.35,49.42,32.99,26.08,24.94,14.26, 14.16.
IR(neat)2926.80,1736.92,1686.34,1557.79,1291.40,1252.96,1128.22, 1132.99.
HRMS(ESI+)calcd for C23H29N2O4:397.2127,found:397.2112.
Embodiment 16
Novel compounds C is prepared according to 1 the method for embodiment24H24N2O4, products collection efficiency 30%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.02–7.97(m,2H),7.46–7.37(m,5H),7.36– 7.30 (m, 2H), 7.28-7.23 (m, 1H), 7.02 (s, 1H), 4.87 (d, J=5.6Hz, 2H), 4.38 (q, J=7.2Hz, 2H), 4.31 (q, J=7.2Hz, 2H), 1.39 (t, J=7.2Hz, 3H), 1.33 (t, J=7.1Hz, 3H)
13C NMR(101MHz,cdcl3)δ168.88,166.73,159.86,157.83,145.99,139.79, 138.15,130.17,128.71,128.64,127.65,127.42,127.12,106.86,101.20,61.92,61.51, 45.28,14.26,14.12.
IR(neat)2957.73,1735.82,1686.32,1557.79,1289.04,1251.75,1131.77, 1028.66.
HRMS(ESI+)calcd for C24H25N2O4:405.1814,found:405.1797.
Embodiment 17
Novel compounds C is prepared according to 1 the method for embodiment24H24N2O5, products collection efficiency 27%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ9.85(s,1H),8.02(M,2H),7.61(M,2H),7.45(M,3H),7.15 (s,1H),6.93(M,2H),4.38(M,4H),3.83(s,3H),1.39(M,6H).
13C NMR(101MHz,cdcl3)δ168.62,166.87,159.78,155.79,155.68,146.10, 137.94,132.77,130.32,128.85,127.48,123.13,114.02,108.30,102.00,62.05,61.90, 55.66,14.29,14.13.
IR(neat)2920.62,1736.39,1687.37,1579.82,1510.09,1370.47,1302.32, 1184.16.
HRMS(ESI+)calcd for C24H25N2O5:421.1763,found:421.1743.
Embodiment 18
Novel compounds C is prepared according to 1 the method for embodiment19H22N2O4, products collection efficiency 65%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3)δ8.10–8.01(m,2H),7.92(s,1H),7.54–7.39(m,3H),7.00 (s,1H),3.90(s,3H),3.84(s,3H),1.57(s,9H).
13C NMR(101MHz,cdcl3)δ169.50,167.42,159.41,157.79,145.55,138.37, 130.08,128.77,127.35,105.76,101.06,52.79,52.36,51.90,29.29.
IR(neat)2958.10,1737.77,1693.33,1588.12,1559.40,1356.05,1256.64, 1129.43.
HRMS(ESI+)calcd for C19H23N2O4:343.1658,found:343.1639.
Embodiment 19
Novel compounds C is prepared according to 1 the method for embodiment19H22N2O4, products collection efficiency 57%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,cdcl3)δ8.13–7.97(m,2H),7.83(s,1H),7.51–7.37(m,3H),6.99 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.65 (td, J=7.0,5.6Hz, 2H), 1.75-1.59 (m, 2H), 1.47 (dd, J=15.1,7.4Hz, 2H), 0.98 (t, J=7.3Hz, 3H)
13C NMR(101MHz,cdcl3)δ169.48,167.19,160.04,158.11,145.60,138.25, 130.20,128.74,127.38,106.12,100.70,52.80,52.35,41.07,31.72,20.46,14.07.
IR(neat)2960.82,1740.85,1693.22,1560.00,1350.58,1251.33,1128.84, 1080.45.
HRMS(ESI+)calcd for C19H23N2O:343.1658,found:343.1640.
Embodiment 20
Novel compounds C is prepared according to 1 the method for embodiment21H24N2O4, products collection efficiency 67%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.12-7.97 (m, 2H), 7.82 (d, J=7.2Hz, 1H), 7.57-7.37 (m, 3H),6.97(s,1H),4.33–4.15(m,1H),3.91(s,3H),3.84(s,3H),2.13–2.02(m,2H),1.88– 1.70(m,2H),1.54–1.30(m,6H).
13C NMR(101MHz,cdcl3)δ169.52,167.16,160.02,157.38,145.70,138.28, 130.17,128.76,127.34,105.95,100.43,52.79,52.32,49.48,32.98,26.07,24.94.
IR(neat)2932.99,1740.59,1692.87 1557.69,1350.64,1294.93,1253.68, 1129.83.
HRMS(ESI+)calcd for C21H25N2O4:369.1814,found:369.1799.
Embodiment 21
Novel compounds C is prepared according to 1 the method for embodiment28H37N3O6, products collection efficiency 60%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 7.99 (dd, J=8.6,1.4Hz, 2H), 7.89 (d, J=7.2Hz, 1H), 7.45 (d, J=7.8Hz, 2H), 6.90 (s, 1H), 6.65 (s, 1H), 4.36 (q, J=7.2Hz, 2H), 4.30 (q, J=7.1Hz, 2H),4.25–4.16(m,1H),2.15–2.03(m,2H),1.84–1.70(m,2H),1.71–1.60(m,2H),1.54(s, 8H),1.45–1.29(m,10H).
13C NMR(101MHz,cdcl3)δ169.93,169.21,166.83,159.20,157.42,152.56, 146.02,140.28,132.87,128.23,118.19,105.33,61.83,61.27,49.48,32.98,28.45, 27.04,26.10,24.97,14.26,14.18.
IR(neat)2957.73,1736.08,1560.60,1527.00,1371.55,1324.94,1296.36, 1180.65.
HRMS(ESI+)calcd for C28H38N3O6:512.27551,found:512.27502.
Embodiment 22
Novel compounds C is prepared according to 1 the method for embodiment26H31N5O5, products collection efficiency 65%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.20 (d, J=7.2Hz, 2H), 8.05 (s, 1H), 7.91 (d, J=7.1Hz, 1H), 7.84 (d, J=7.2Hz, 2H), 6.98 (s, 1H), 4.92 (s, 2H), 4.44-4.29 (m, 4H), 4.27-4.20 (m, 1H),2.17–2.02(m,2H),1.86–1.65(m,4H),1.56–1.42(m,8H),1.44–1.30(m,8H).
13C NMR(101MHz,cdcl3)δ168.84,166.68,158.01,157.40,146.27,138.83, 137.97,128.79,120.57,105.94,101.32,62.01,61.55,56.88,49.57,32.93,26.06,24.93, 14.28,14.16.
IR(neat)2953.77,296.11,1737.11,1687.28,1559.70,1347.24,1254.83, 1131.59.
HRMS(ESI+)calcd for C26H32N5O5:494.23980,found:494.23917.
Embodiment 23
Present embodiments provide a kind of known compound 2- spy fourth amino -3- phenyl isoquinolin quinoline, molecular formula are as follows: C19H20N2, structural formula are as follows:
The compound synthesizes to obtain using following specific steps:
{ Rh (COD) Cl } is sequentially added into 5ml reaction tube2(2mg, 0.0038mmol) and 2,2 '-bipyridyls (1mg, 0.0075mmol), Isosorbide-5-Nitrae-dioxane (2ml) after stirring 5min, reuses syringe and (1- nitrine ethylene) base benzene is added (22mg, 0.15mmol), tert-butyl isonitrile (13mg, 17uL, 0.2mmol), reacts 5h at room temperature.After complete reaction, add Enter and trifluoromethanesulfonic acid (2- trimethyl silicon substrate) phenyl ester (89mg, 0.3mmol), KF (17mg, 0.3mmol), 18- is added with syringe Crown- 6- ether (79mg, 0.3mmol) continues the reaction at room temperature for 24 hours, after TLC detection reaction completely.Solvent is concentrated under reduced pressure in system, residual Excess isolates and purifies (petroleum ether: ethyl acetate=100:1) by flash column chromatography, obtains yellow-green liquid 30mg, yield 74%.
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.17 (d, J=8.6Hz, 2H), 7.69 (t, J=7.6Hz, 2H), 7.56-7.51 (m, 1H), 7.47 (t, J=7.6Hz, 2H), 7.42-7.33 (m, 3H), 5.18 (s, 1H), 1.67 (s, 9H)
13C NMR(101MHz,cdcl3)δ154.11,148.84,140.56,138.11,129.48,128.56, 128.06,127.95,126.75,125.57,121.44,117.94,106.11,51.93,29.38.
The method provided using above-described embodiment 23, is only adjusted correspondingly the substituent group of raw material, can be obtained such as Lower 24~34 compound represented of embodiment.
Embodiment 24
Novel compounds C is prepared according to 23 the method for embodiment20H22N2O, products collection efficiency 31%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.11 (d, J=8.7Hz, 2H), 7.67 (d, J=8.2Hz, 2H), 7.55- 7.49 (m, 1H), 7.37 (t, J=7.6Hz, 1H), 7.32 (s, 1H), 7.05-6.98 (m, 2H), 3.87 (s, 4H), 1.66 (s, 11H).
13C NMR(101MHz,cdcl3)δ159.82,154.05,148.63,138.26,133.31,129.43, 127.96,127.75,125.18,121.43,117.59,113.95,104.98,55.48,51.89,29.39.
IR(neat)2957.77,1620.46,1607.44,1569.15,1288.81,1248.53,1275.59, 1180.15.
HRMS(ESI+)calcd for C20H23N2O:307.18049,found:307.17987.
Embodiment 25
Novel compounds C is prepared according to 23 the method for embodiment20H19F3N2, products collection efficiency 51%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.26 (d, J=8.7Hz, 2H), 7.76-7.66 (m, 4H), 7.58 (t, J= 8.1Hz,1H),7.49–7.41(m,2H),5.24(s,1H),1.67(s,9H).
13C NMR (101MHz, cdcl3) δ 154.25,147.35,144.02,137.86,129.76,129.73 (q, J= 32.2Hz), 128.66,126.89,126.23,125.51 (q, J=3.7Hz), 124.60 (q, J=272.0Hz), 121.48, 118.32,107.06,52.02,29.32.
IR(neat)2957.73,1521.17,1414.50,1163.01,1123.06,1070.50,1063.47.
HRMS(ESI+)calcd for C20H20F3N2:345.15731,found:345.15662.
Embodiment 26
Novel compounds C is prepared according to 23 the method for embodiment20H22N2, products collection efficiency 54%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.06 (d, J=8.1Hz, 2H), 7.71-7.64 (m, 2H), 7.57-7.47 (m, 1H), 7.42-7.36 (m, 2H), 7.27 (d, J=7.9Hz, 2H), 5.17 (s, 1H), 2.41 (s, 3H), 1.66 (s, 9H)
13C NMR(101MHz,cdcl3)δ154.07,148.95,138.18,137.88,129.42,129.31, 127.86,126.67,125.35,121.43,117.81,105.62,51.91,29.39,21.42.
IR(neat)2957.11,1621.21,1594.66,1519.92,1445.03,1412.39,1233.44, 1215.01.
HRMS(ESI+)calcd for C20H23N2:291.18558,found:291.18475.
Embodiment 27
Novel compounds C is prepared according to 23 the method for embodiment20H22N2, products collection efficiency 67%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 7.98 (d, J=11.6Hz, 2H), 7.68 (t, J=7.7Hz, 2H), 7.53 (t, J=7.6Hz, 1H), 7.45-7.29 (m, 3H), 7.18 (d, J=7.5Hz, 1H), 5.17 (s, 1H), 2.45 (s, 3H), 1.67 (s,9H).
13C NMR(101MHz,cdcl3)δ154.08,149.04,140.59,138.13,137.94,129.44, 128.83,128.49,127.92,127.50,125.49,124.02,121.43,117.91,106.13,51.92,29.39, 21.89.
IR(neat)2917.53,1621.61,1568.89,1520.89,1417.70,1359.35,1234.89, 1215.54.
HRMS(ESI+)calcd for C20H23N2:291.18558,found:291.18481.
Embodiment 28
Novel compounds C is prepared according to 23 the method for embodiment20H22N2, products collection efficiency 40%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 7.70 (d, J=8.3Hz, 1H), 7.66 (d, J=8.1Hz, 1H), 7.57- 7.52(m,2H),7.46–7.38(m,1H),7.29–7.22(m,3H),6.98(s,1H),5.16(s,1H),2.47(s,3H), 1.58(s,9H).
13C NMR(101MHz,cdcl3)δ153.86,151.84,142.21,137.63,136.09,130.53, 130.14,129.38,127.66,127.42,125.60,125.54,121.39,117.27,110.28,51.92,29.55, 21.01.
IR(neat)2960.82,1622.13,1567.58,1520.82,1420.67,1376.56,1231.52, 1241.77.
HRMS(ESI+)calcd for C20H23N2:291.18558,found:291.18488.
Embodiment 29
Novel compounds C is prepared according to 23 the method for embodiment19H19FN2, products collection efficiency 53%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR (400MHz, cdcl3) δ 8.17-8.08 (m, 2H), 7.68 (d, J=8.2Hz, 2H), 7.57-7.50 (m, 1H),7.44–7.36(m,1H),7.33(s,1H),7.18–7.11(m,2H),5.20(s,1H),1.66(s,9H).
13C NMR (101MHz, cdcl3) δ 163.03 (d, J=246.7Hz), 154.13,147.91,138.07, (136.70,129.58,128.36 d, J=8.1Hz), 127.86,125.61,121.44,117.81,115.34 (d, J= 21.3Hz),105.71,51.92,29.34.
IR(neat)2967.01,1602.67,1569.90,1512.27,1444.90,1433.74,1412.95, 1230.77.
HRMS(ESI+)calcd for C19H20FN2:295.16050,found:295.16003.
Embodiment 30
Novel compounds C is prepared according to 23 the method for embodiment19H19ClN2, products collection efficiency 51%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.03 (d, J=8.6Hz, 2H), 7.71-7.65 (m, 2H), 7.58 (d, J= 8.5Hz,2H),7.56–7.51(m,1H),7.45–7.38(m,1H),7.37(s,1H),5.20(s,1H),1.65(s,9H).
13C NMR(101MHz,cdcl3)δ154.16,147.75,139.55,137.98,131.65,129.65, 128.35,127.96,125.85,122.20,121.46,118.04,106.08,51.96,29.33.
IR(neat)2957.73,1621.53,1594.85,1521.01,1443.87,1406.13,1232.21, 1215.73.
HRMS(ESI+)calcd for C19H20ClN2:311.13095,found:311.13034.
Embodiment 31
Novel compounds C is prepared according to 23 the method for embodiment19H19BrN2, products collection efficiency 50%；Compound structure Formula are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.09 (d, J=8.7Hz, 2H), 7.69 (d, J=8.8Hz, 2H), 7.55 (t, J =7.6Hz, 1H), 7.45-7.39 (m, 3H), 7.37 (s, 1H), 5.21 (s, 1H), 1.66 (s, 9H)
13C NMR(101MHz,cdcl3)δ154.15,147.69,139.06,137.98,133.88,129.64, 128.69,127.99,127.94,125.81,121.46,118.00,106.07,51.95,29.33.
IR(neat)2963.92,1621.28,1572.22,1522.46,1449.98,1432.54,1231.94, 1217.38.
HRMS(ESI+)calcd for C19H20BrN2:355.08044,found:355.07974.
Embodiment 32
Novel compounds C is prepared according to 23 the method for embodiment19H20N2, products collection efficiency 70%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.17 (d, J=7.6Hz, 2H), 7.71 (d, J=8.2Hz, 2H), 7.59-7.51 (m,1H),7.50–7.32(m,5H),5.25(s,1H),3.75(s,2H),1.84–1.68(m,2H),1.60–1.44(m,2H), 1.01 (t, J=7.8Hz, 3H)
13C NMR(101MHz,cdcl3)δ154.85,138.15,129.78,128.57,128.21,127.79, 126.78,125.64,121.50,117.50,106.58,31.93,29.84,20.60,14.17.
Embodiment 33
Novel compounds C is prepared according to 23 the method for embodiment21H22N2, products collection efficiency 64%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.15 (d, J=7.9Hz, 2H), 7.71 (d, J=8.7Hz, 2H), 7.58-7.51 (m, 1H), 7.49-7.32 (m, 5H), 5.13 (d, J=6.6Hz, 1H), 4.43-4.28 (m, 1H), 2.26 (d, J=8.9Hz, 2H), 1.82 (d, J=13.6Hz, 2H), 1.71 (d, J=12.9Hz, 1H), 1.61-1.44 (m, 2H), 1.42-1.17 (m, 3H).
13C NMR(101MHz,cdcl3)δ154.03,149.13,140.45,138.23,129.66,128.57, 128.14,127.80,126.74,125.51,121.40,117.45,106.32,49.91,33.47,26.23,25.33.
Embodiment 34
Novel compounds C is prepared according to 23 the method for embodiment22H18N2, products collection efficiency 74%；Structural formula of compound Are as follows:
The characterize data of gained compound includes:
1H NMR(400MHz,CDCl3) δ 8.15 (d, J=7.4Hz, 2H), 7.77-7.71 (m, 2H), 7.58 (t, J= 7.6Hz, 1H), 7.53-7.34 (m, 9H), 7.30 (t, J=7.3Hz, 1H), 5.52 (s, 1H), 4.98 (d, J=5.3Hz, 2H)
13C NMR(101MHz,cdcl3)δ156.82,154.47,149.07,140.21,140.13,138.21, 129.89,128.78,128.59,128.27,127.85,127.40,126.81,125.80,121.50,117.44,107.21, 46.09.
IR(neat)2954.64,1621.14,1566.94,1521.93,1453.54,1379.44,1356.99, 1174.19.
HRMS(ESI+)calcd for C22H19N2:311.15428,found:311.15353.
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art 's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed Range.

Claims (10)

1. a kind of preparation method of polysubstituted nitrogenous heteroaromatic compound, which is characterized in that the polysubstituted nitrogenous fragrance is miscellaneous Cycle compound has the structure such as logical formula (I) or (II):
In the logical formula (I) or (II), R1~R6It is each independently selected from hydrogen atom, two substituted amidos, amide groups, ester group, ketone carbonyl Base, siloxy, halogen, aryl, heteroaryl, naphthenic base, heterocycle, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, Cycloalkyl-alkyl, heterocyclylalkyl group or aryl-alkoxy-alkyl；And the R1~R6In, at least two groups are not hydrogen atom；
The reaction mechanism mechanism of reaction of the method are as follows:
It comprises the following specific steps that: transition-metal catalyst, 2,2 '-bipyridine ligands and solvent being added into reaction vessel, Raw material A and raw material B are added after mixing, sufficiently adds the precursor of raw material C or raw material D or raw material D after reaction at room temperature, Under the conditions of -10 DEG C~150 DEG C sufficiently react to get.
2. the method according to claim 1, wherein the excessive metalcatalyzing agent is palladium catalyst or rhodium catalysis Agent；
Preferably, the palladium catalyst be Metal Palladium, palladium salt, palladium with contain Phosphine ligands, containing n-donor ligand, oxygen-containing ligands, sulfur-containing ligand One of or the complex or supported palladium of alkenyl ligand composition, more preferably but be not limited to following collection: palladium carbon, palladium oxide, hydrogen Palladium oxide, palladium/titanium dioxide, Pd/Ph-SBA-15, Pd-BTP/SiO2, material load Pd, SiO2Pd is loaded, Lindla is urged Agent, Pd/BaSO4, Pd/CaCO3, high molecular material load Pd；And/or the rhodium catalyst be metal rhodium, rhodium salt, rhodium with contain The complex or load rhodium that phosphorus ligand, containing n-donor ligand, oxygen-containing ligands, phosphorus-containing ligand, sulfur-containing ligand or alkenyl ligand form, it is more excellent One of select but be not limited to following collection: rhodium carbon, triphenylphosphine radium chloride, { Rh (COD) Cl }2,{Rh(COD)OH}2,Rh (COD)(acac),{Rh(NBD)Cl}2。
3. method according to claim 1 or 2, which is characterized in that the dosage of the transition-metal catalyst is raw material A matter 0.001~5%, preferably 0.01~2.5%, more preferably the 0.05~0.1% of amount.
4. method according to any one of claims 1 to 3, which is characterized in that the reaction dissolvent is water, dichloromethane Alkane, 1,2- dichloroethanes, chloroform, ether, tetrahydrofuran, 1,4- dioxane, methyl n-butyl ether, methanol, ethyl alcohol, isopropyl One of alcohol, benzene, toluene, acetonitrile, nitromethane, pentane, hexane are a variety of；
And/or the reaction temperature is 120 DEG C~130 DEG C.
5. method described in any one according to claim 1~4, it is characterised in that: after fully reacting, concentration removal solvent, Residue purified to get；
The purifying is preferably the combination of one of column chromatography, vacuum distillation, recrystallization or a variety of methods；
The purifying is more preferably: the mobile phase formed using petroleum ether and ethyl acetate is carried out after column chromatography is separated Vacuum distillation or recrystallization.
6. a kind of polysubstituted nitrogenous heteroaromatic compound, which is characterized in that have the structure such as logical formula (I) or (II):
In the logical formula (I) or (II), R2And R6It is hydrogen atom, R1、R3、R4、R5It is each independently selected from ester group, aryl, miscellaneous Aryl, naphthenic base, heterocycle, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclylalkyl group or Aryl-alkoxy-alkyl.
7. compound according to claim 6, which is characterized in that the R3、R4It is ester group.
8. compound according to claim 6 or 7, which is characterized in that the R1Selected from aryl, heteroaryl, naphthenic base, miscellaneous Ring group, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclylalkyl group or aryl-alkoxy-alkyl；
And/or the R5Selected from alkyl, naphthenic base, substituted or unsubstituted aryl.
9. compound according to claim 6, which is characterized in that be selected from one of following compound or a variety of:
10. described in compound or claim 6~9 any one that Claims 1 to 5 any one the method is prepared Compound preparing the application in fluorescent marker.
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CN113135840A (en) * 2021-04-28 2021-07-20 江西师范大学 Synthetic method of conjugated alkenyl amidine compound

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CN112174877A (en) * 2020-10-13 2021-01-05 华侨大学 Preparation method of 2, 4-diaryl-6-trifluoromethylpyridine derivative
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