CN108373448A - A kind of microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides - Google Patents
A kind of microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides Download PDFInfo
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- CN108373448A CN108373448A CN201810370964.3A CN201810370964A CN108373448A CN 108373448 A CN108373448 A CN 108373448A CN 201810370964 A CN201810370964 A CN 201810370964A CN 108373448 A CN108373448 A CN 108373448A
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- quinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to organic synthesis fields, specifically disclose a kind of microwave assisted synthesizing method of N (2 base of quinoline) aromatic amides, the positions the C2 N amidation process of Quinoline N-Oxide occurs under lignin sulfonic acid and microwave radiation technology for Quinoline N-Oxide, aromatic nitriles, obtains described N (2 base of the quinoline) aromatic amides.This method raw material is easy to get, and reaction condition simplicity, mild, green energy conservation, reaction selectivity and yield are high, substrate functional group excellent compatibility；Especially lignin sulfonic acid is as acid catalyst, and not only easily recycling is reused, and reduces reaction cost, it is thus also avoided that the pollution problem of the Protic Acid Catalyzed reaction of tradition has higher application value.
Description
Technical field
It is the present invention relates to a kind of microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides, more particularly to a kind of micro-
The method that wave radiation assists Quinoline N-Oxide amidation process synthesis N- (quinoline -2- bases) aromatic amides, belonging to has
Machine intermediate synthesis technical field.
Background technology
N- (quinoline -2- bases) aromatic amides have preferable pharmacological activity, as active anticancer (Nat.Chem.2017,9,
1110), antibacterial activity (J.Med.Chem.2017,60,9,3755), antianaphylaxis (J.Med.Chem.1988,31,6,
1098), the agent of Trinucleotide repeats extension inhibition from mutation (Bioorg.Med.Chem.Lett.2016,26,15,3761,
J.Am.Chem.Soc.2005,127,12657) etc..Simultaneously N- (quinoline -2- bases) aromatic amides in organic synthesis field, and
Extraordinary organic synthesis intermediate.Therefore, there is important meaning to the research of the synthetic method of N- (quinoline -2- bases) aromatic amides
Justice.
The synthetic method of N- (quinoline -2- bases) aromatic amides is broadly divided into following three classes at present：
1) 2- aminoquinolines aroylation reaction (J.Am.Chem.Soc.2000,122,2172；
J.Am.Chem.Soc.2001,123,12650；Chem.Commun.2014,50,15094), 2- halogenated quinolines are coupled with amide
Reaction (J.Org.Chem.2005,70,8764；RSC Adv.2013,3,18787), there are quinoline originals for the type reaction
Expect that type is limited；Reaction usually requires alkaline condition, the unstable functional group's susceptible of alkalinity.
2) based on quinoline nitrogen villiaumite amidation process (Synth.Commun.1994,24,2387, Tetrahedron
Lett.2005,46,4487；Russ.Chem.Bull., 2016,65,2312).The course of the type reaction is usually ultralow
Under the conditions of temperature, fluorine gas fluoroquinolines obtain quinoline nitrogen villiaumite intermediate, then obtain N- (quinoline -2- bases) acetyl with acetonitrile reaction
Amine.Such reacts the preparation that only reported N- (quinoline -2- bases) acetamide compound, and maximum output only 55%；Fluorine gas has
The characteristics such as severe toxicity, highly corrosive, explosive, the serious application for restricting this method.
3) based on Quinoline N-Oxide and amide coupling reaction (J.Org.Chem., 2009,74,1341,
Org.Lett., 2006,8,1929).
Although this method raw material Quinoline N-Oxide source is easy to get, the severe reaction conditions of the type reaction, not only
It needs to use volatile toxic dichloromethane as reaction medium, also need using oxalyl chloride or three fluorosulfonic anhydrides and 2- fluorine pyrroles
Pyridine not only increases reaction cost as auxiliary agent, also results in environment side effect.
Invention content
Insufficient present in traditional technology in order to overcome, the purpose of the present invention is be intended to provide a kind of can not only improve instead
Efficiency is answered, production cost is reduced, N- (quinoline -2- bases) environmental-friendly preparation of aromatic amides of reaction three waste discharge can also be reduced
Method.
In order to achieve the above technical purposes, the present invention provides a kind of microwave radiation technologies of N- (quinoline -2- bases) aromatic amides
Synthetic method, for this method using Quinoline N-Oxide as reaction substrate, aromatic nitriles are N- amidation reagents, and lignin sulfonic acid is catalysis
Agent, microwave radiation auxiliary is lower to carry out N- amidation process, obtains N- (quinoline -2- bases) aromatic amides.
The preparation method will be R with the Quinoline N-Oxide of structure shown in formula 1 and expression formula1The aromatic nitriles of CN,
Under the catalytic action in microwave radiation and sulfonic acid source, the positions the C2 N- amidation process of Quinoline N-Oxide is carried out, is obtained with formula 2
N- (quinoline -2- bases) aromatic amides of structural formula；
The R1For the aryl of C6~C20 or the heterocyclic aryl of C5~C20, allow on the aryl, heterocyclic aryl
At least one of the alkoxy of alkyl, C1~C6 containing C1~C6, halogen, cyano substituent group；
The R2~R6It is alkynes base, the C1 of the alkyl of H, C1~C20, the alkylene of C1~C20, C1~C20 alone
Either the undersaturated cyclic hydrocarbon radical in part, the saturation of C5~C20 or part are unsaturated for the alkoxy of~C20, the saturation of C5~C20
Heterocyclic hydrocarbyl, the aryl of C6~C20, the heterocyclic aryl of C5~C20, ester group or halogen；
The alkyl, alkynes base, cyclic hydrocarbon radical, heterocyclic hydrocarbyl, aryl, allows containing C1 on heterocyclic aryl alkylene
At least one of~C6 alkoxies, C1~C6 alkyls, halogen substituent group；
Alternatively, R3~R6Middle any two adjacent group is constituted together comprising five yuan or hexa-atomic portion including quinoline carbon
Divide unsaturated cyclic structure；
Or R3~R6Middle any two adjacent group constitutes the condensed cyclic structure with quinoline ring conjugation, the condensed ring together
Allow the hetero atom containing at least one of N, O, S hydridization in structure；
The sulfonic acid source is at least provided with a sulfonic material.
Core of the invention is the cooperation of the sulfonic acid source and microwave irradiation synthesis method.The study found that using
The microwave irradiation synthesis of the sulfonic acid source cooperation present invention, can be obviously improved the yield of product, shorten the reaction time, hence it is evident that improve synthesis
Efficiency.
In the present invention, the alkyl of the C1~C20 is the straight chain or branched alkane alkyl of the carbon number, the C2~
The alkylene of C20 is that at least there are one the hydrocarbyl groups of carbon-carbon double bond for tool, for example, allyl, acrylic etc.；Described is described
The alkynes base of C2~C20 is that at least there are one the hydrocarbyl groups of triple carbon-carbon bonds for tool, for example, propargyl；The virtue of the C6~C10
Base is, for example, phenyl or multiple phenyl ring and the condensed ring group for closing formation, such as naphthalene.
Either the undersaturated naphthenic base in part is, for example, five yuan or hexa-atomic cyclic group to C5~C20 saturations, described
The carbon that cyclic group constitutes ring can be saturated carbon or part unsaturated carbon.
The saturation of C5~C20 either for example, five yuan of the undersaturated heterocyclic hydrocarbyl in part or hexa-atomic cyclic group, institute
The carbon that the cyclic group stated constitutes ring can be replaced by hetero atom hydridization, and it can be saturated carbon to constitute the carbon of ring and/or hetero atom
Or part unsaturated carbon.
The heterocyclic aryl of C5~C20 be, for example, five yuan or it is hexa-atomic there is heteroatomic aromatic group, heterocyclic aryl
Hetero atom is, for example, N, S or O.
Preferably, the R1For phenyl, five-ring heterocycles aryl or hexa-member heterocycle aryl.Still more preferably,
The R1For phenyl, furans, thiophene；Or at least one of C1~C3 alkyl, C1~C3 alkoxies, halogen substituent group take
Phenyl, furans or the thiophene in generation.
The R2~R6It is the alkyl of H, C1~C20, the alkoxy of C1~C20, ester group, nitro or halogen alone；
Alternatively, R3~R6Middle any two adjacent group constitutes three~five rings condensed-nuclei aromatics with quinoline ring conjugation together.
Further preferably, the R2~R6It is the alkyl of H, C1~C6, the alkoxy of C1~C6, ester group, nitro alone
Or halogen；Still more preferably it is H, methyl, ethyl, methoxyl group, ethyoxyl, carbomethoxy, halogen or nitro；Further preferably,
The R2~R6In, 1~2 substituent group therein is methyl, ethyl, methoxyl group, ethyoxyl, carbomethoxy, halogen or nitre
Base；Most preferably, R2For H.
Alternatively, R3-R4、R4-R5Or R5-R6The tricyclic condensed-nuclei aromatics with quinoline ring conjugation is constituted together.
Preferably, the Quinoline N-Oxide has formula 1-A structures：
In formula 1-A, R7For the substituent group for removing on any position other than 2,3 on quinoline ring；
R7For the alkyl of H, C1~C6, the aryl of C6~C20, the alkoxy of C1~C6, the ester group of C2~C6, nitro or halogen
Plain substituent group.
Core of the invention is the cooperation of the sulfonic acid source and microwave assisted synthesizing method.The study found that using
The sulfonic acid source, cooperation microwave assisted synthesizing method of the invention, can be obviously improved the yield of product, shorten the reaction time, hence it is evident that
Improve combined coefficient.
Preferably, the sulfonic acid source is p-methyl benzenesulfonic acid or lignin sulfonic acid；Preferably lignin sulfonic acid.
It is more excellent using lignin sulfonic acid and microwave cooperating effect, the yield higher of product.
Preferably, the quality of lignin sulfonic acid is not less than the 10% of Quinoline N-Oxide quality；Preferably 10-30%.
Further preferably, it is 20~30% that the quality of lignin sulfonic acid, which is Quinoline N-Oxide quality,.It is preferred at this
Under range, the yield higher of product.
In the present invention, aromatic nitrile compounds are not less than the theoretical amount for reacting Quinoline N-Oxide completely.
Preferably, the molar ratio 1: 5~10 of Quinoline N-Oxide and aromatic nitrile compounds.
Further preferably, the molar ratio 1: 7.5~10 of Quinoline N-Oxide and aromatic nitrile compounds.In the preferred molar ratio
Under, the yield of product is further promoted, and yield may be up to 92% or more.
As preferred：In reaction process, without additional addition reaction dissolvent.
As preferred：The power of microwave is not less than 100W；Preferably 100~300W.
Further preferably, the power of microwave is 150~300W.The study found that under the range microwave reaction yield compared with
It is high.Further study show that the power of microwave is preferably 150W.Under the preferred power, reacts and moved to positive direction, target
The yield of product is obviously improved.
The preferred microwave-assisted reaction time is 15~30 minutes.
A kind of microwave assisted synthesizing method of preferred N- (quinoline -2- bases) aromatic amides of the present invention, Quinoline N-Oxide
With aromatic nitriles (R1CN), under microwave radiation and sulfomethylated lignin acid catalysis, the positions the C2 N- amides of Quinoline N-Oxide are carried out
Change reaction, obtains N- (quinoline -2- bases) aromatic amides.
The route square formula 1 of synthesis：
Compared with the prior art, the advantageous effects that technical scheme of the present invention is brought：
1) Quinoline N-Oxide and aromatic nitriles initial feed derive from a wealth of sources；
2) using cheap lignin sulfonic acid as catalyst, one side catalytic activity is high, can improve nitrogen oxides amide
Change reaction efficiency；On the other hand, pass through simple filtration, you can recycling catalyst is simultaneously reused, and is not only effectively reduced cost, also
It avoids using problem of environmental pollution caused by other bronsted acid catalysts；
3) microwave radiation assisted reaction is used, while shortening the reaction time, improves reaction yield；
4) reaction carries out under solvent-free conditions, and production cost is not only greatly saved, it is thus also avoided that environmental pollution；
5) reaction is recovered under reduced pressure unreacted with not having any by-product to generate in the reaction of 100% atomic efficiency
N- (quinoline -2- bases) aromatic amides sterling can both be obtained by being recrystallized after aromatic nitriles.
Specific implementation mode
Following specific examples is intended to further illustrate the content of present invention, rather than limits the protection of the claims in the present invention
Range.
Following embodiment and comparative example, the mass fraction refer to sulfonic acid source (lignin sulfonic acid or p-methyl benzenesulfonic acid)
For the mass ratio of Quinoline N-Oxide raw material.
Embodiment 1
The preparation of N- (quinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), benzene
Formonitrile HCN 7.65mL (7.73g, 75mmol), 20% mass fraction lignin sulfonic acid (that is to say that lignin sulfonic acid is quinoline nitrogen oxidation
The 20% of amount of substance), gained mixture is stirred to react l50W microwave radiations in device in microwave and reacts 20 minutes.It is recovered by filtration anti-
The lignin sulfonic acid in system is answered, unreacted benzonitrile in reaction system is recovered under reduced pressure, recrystallizes to obtain N- (quinoline -2- bases) benzene
Formamide 2.38g, yield 96%.
Embodiment 2
It is compared with embodiment 1, the main distinction is, 150W microwave radiation assisted reactions are replaced with 100W microwave radiations：
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 100W microwaves in device in microwave
Radioreaction 40 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 1.93g, yield 78%.
Embodiment 3
It is compared with embodiment 1, the main distinction is, 150W microwave radiation assisted reactions are replaced with 300W microwave radiations：
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 300W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 2.38g, yield 96%.
Embodiment 4
It is compared with embodiment 1, the main distinction is, 20% mass fraction wood is replaced with 10% mass fraction lignin sulfonic acid
Quality sulfonic acid
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 10% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 2.03g, yield 82%.
Embodiment 5
It is compared with embodiment 1, the main distinction is, 20% mass fraction wood is replaced with 30% mass fraction lignin sulfonic acid
Quality sulfonic acid
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 30% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 2.38g, yield 96%.
Embodiment 6
It is compared with embodiment 1, the main distinction is, is reacted with p-methyl benzenesulfonic acid and replaces lignin sulfonic acid：
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), p-methyl benzenesulfonic acid 2.58g (15mmol), gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.Unreacted benzonitrile in reaction system is recovered under reduced pressure, it is not anti-that saturated aqueous sodium carbonate neutralization is added
The p-methyl benzenesulfonic acid answered, ethyl acetate extract liquid separation, collect organic phase, ethyl acetate is removed under reduced pressure, recrystallizes to obtain N- (quinoline-
2- yls) benzamide 1.98g, yield 80%.
Embodiment 7
It is compared with embodiment 1, the main distinction is, 7.5 times of stoichiometric benzene are replaced with 5 times of stoichiometric benzonitriles
Formonitrile HCN
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 5.10mL are sequentially added
(5.15g, 50mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 1.26g, yield 51%.
Embodiment 8
It is compared with embodiment 1, the main distinction is, stoichiometric with 10 times of stoichiometric 7.5 times of benzonitriles replacements
Benzonitrile
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 10.21mL are sequentially added
(10.3g, 100mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 300W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (quinoline -2- bases) benzamide 2.38g, yield 96%.
Comparative example 1
It is compared with embodiment 1, the main distinction is, is stirred to react with 100 DEG C and replaces microwave radiation assisted reaction：
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 24 hours at 100 DEG C.Thin layer
Analysis method analysis finds that nearly 2- (1H)-quinolinone target product generates, and liquid chromatogram normalization method analyzes to obtain N- (quinoline -2- bases) benzene first
Amide yield is less than 10%.
Comparative example 2
It is compared with embodiment 1, the main distinction is, does not add acid catalyst of the present invention：
In 25mL round-bottomed flasks, Quinoline N-Oxide 1.45g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), gained mixture are stirred to react 150W microwave radiations in device in microwave and react 40 minutes.Thin-layer chromatography
Method analysis finds that no target product generates.
Embodiment 9
The preparation of N- (4- methylquinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 4- methylquinoline nitrogen oxides 1.59g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (4- methylquinoline -2- bases) benzamide 2.49g, yield 95%.
Embodiment 10
The preparation of N- (6- methylquinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 6- methylquinoline nitrogen oxides 1.59g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (6- methylquinoline -2- bases) benzamide 2.49g, yield 95%.
Embodiment 11
The preparation of N- (8- methylquinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 8- methylquinoline nitrogen oxides 1.59g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (8- methylquinoline -2- bases) benzamide 2.41g, yield 92%.
Embodiment 12
The preparation of N- (6- methoxy quinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 6- methoxy quinoline nitrogen oxides 1.75g (10mmol), benzonitrile are sequentially added
7.65mL (7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react in microwave in device
150W microwave radiations react 20 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, is recovered under reduced pressure in reaction system not anti-
The benzonitrile answered recrystallizes to obtain N- (6- methoxy quinoline -2- bases) benzamide 2.67g, yield 96%.
Embodiment 13
The preparation of N- (6- phenylchinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 6- phenylchinoline nitrogen oxides 2.21g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 15% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (6- phenylchinoline -2- bases) benzamide 3.11g, yield 96%.
Embodiment 14
The preparation of N- (6- bromoquinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, 6- bromoquinoline N-oxides 2.23g (10mmol), benzonitrile 7.65mL are sequentially added
(7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react 150W microwaves in device in microwave
Radioreaction 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, unreacted benzene first in reaction system is recovered under reduced pressure
Nitrile recrystallizes to obtain N- (6- bromoquinoline -2- bases) benzamide 3.04g, yield 93%.
Embodiment 15
The preparation of 2-benzamide base quinoline -6- methyl formates：
In 25mL round-bottomed flasks, 6- methyl formate Quinoline N-Oxide 2.03g (10mmol), benzonitrile are sequentially added
7.65mL (7.73g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react in microwave in device
150W microwave radiations react 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, is recovered under reduced pressure in reaction system not anti-
The benzonitrile answered recrystallizes to obtain 2-benzamide base quinoline -6- methyl formate 2.87g, yield 94%.
Embodiment 16
The preparation of 2- methyl-N- (quinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), 2-
Methyl benzonitrile 8.88mL (8.78g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are anti-in microwave stirring
150W microwave radiations in device are answered to react 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, reactant is recovered under reduced pressure
Unreacted 2- methyl benzonitriles in system recrystallize to obtain 2- methyl-N- (quinoline -2- bases) benzamide 2.41g, yield 92%.
Embodiment 17
The preparation of 4- methyl-N- (quinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), 4-
Methyl benzonitrile 8.96mL (8.78g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are anti-in microwave stirring
150W microwave radiations in device are answered to react 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, reactant is recovered under reduced pressure
Unreacted 4- methyl benzonitriles in system recrystallize to obtain 4- methyl-N- (quinoline -2- bases) benzamide 2.51g, yield 96%.
Embodiment 18
The preparation of the fluoro- N- of 4- (quinoline -2- bases) benzamide：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), 4-
Fluorobenzonitrile 9.08g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture is stirred to react in microwave in device
150W microwave radiations react 25 minutes.The lignin sulfonic acid in reaction system is recovered by filtration, is recovered under reduced pressure in reaction system not anti-
The 4- fluorobenzonitriles answered recrystallize to obtain the fluoro- N- of 4- (quinoline -2- bases) benzamide 2.55g, yield 96%.
Embodiment 19
The preparation of N- (quinoline -2- bases) furans -2- formamides：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), 2-
Cyanofuran 6.56mL (6.98g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react in microwave
150W microwave radiations react 20 minutes in device.The lignin sulfonic acid in reaction system is recovered by filtration, reaction system is recovered under reduced pressure
In unreacted 2- cyanofurans, recrystallize to obtain N- (quinoline -2- bases) furans -2- formamide 2.21g, yield 93%.
Embodiment 20
The preparation of N- (quinoline -2- bases) thiophene -3- formamides：
In 25mL round-bottomed flasks, sequentially add Quinoline N-Oxide (in formula 1, R2~R6For H) 1.45g (10mmol), 3-
Cyano thiophene 6.82mL (8.18g, 75mmol), 20% mass fraction lignin sulfonic acid, gained mixture are stirred to react in microwave
150W microwave radiations react 20 minutes in device.The lignin sulfonic acid in reaction system is recovered by filtration, reaction system is recovered under reduced pressure
In unreacted 3- cyano thiophenes, recrystallize to obtain N- (quinoline -2- bases) thiophene -3- formamide 2.38g, yield 94%.
It is found by above example and comparative example, it, can efficiently, in high yield under technical solutions according to the invention
Obtain N- (quinoline -2- bases) aromatic amides.
It is found by each embodiment and comparative example 1,2, the success of the sulfonic acid source and microwave radiation technology to the present invention
It prepares most important.
Further research summarize obtains, microwave power at 100~300W, can obtain good yield (embodiment 1~
3)；Wherein, by microwave power control at 150~300W, the yield of product can be higher than 90%.
The type in p-sulfonic acid source is selected, and higher yield (embodiment 1 and 6), wherein lignin sulfonic acid can be obtained
Effect it is more excellent, in addition, the usage amount to lignin sulfonic acid controls, help further to promote product yield (embodiment
Isosorbide-5-Nitrae, 5) wherein, dosage is more than 10%, and the yield of product may be up to 90%.
In addition, the ratio to raw material controls, can help to further obtain in high yield (embodiment 1,7,8).
Claims (9)
1. a kind of microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides, it is characterised in that：There to be knot shown in formula 1
The Quinoline N-Oxide and expression formula of structure are R1The aromatic nitriles of CN carry out quinoline under the catalytic action in microwave radiation and sulfonic acid source
The positions the C2 N- amidation process of quinoline nitrogen oxides obtains N- (quinoline -2- bases) aromatic amides with 2 structural formula of formula；
The R1For the aryl of C6~C20 or the heterocyclic aryl of C5~C20, allow containing C1 on the aryl, heterocyclic aryl
At least one of the alkyl of~C6, the alkoxy of C1~C6, halogen, cyano substituent group；
The R2~R6Alone be the alkyl of H, C1~C20, the alkylene of C1~C20, the alkynes base of C1~C20, C1~
Either the undersaturated cyclic hydrocarbon radical in part, the saturation of C5~C20 or part are undersaturated for the alkoxy of C20, the saturation of C5~C20
Heterocyclic hydrocarbyl, the aryl of C6~C20, the heterocyclic aryl of C5~C20, ester group or halogen；
The alkyl, alkynes base, cyclic hydrocarbon radical, heterocyclic hydrocarbyl, aryl, allows containing C1~C6 on heterocyclic aryl alkylene
At least one of alkoxy, C1~C6 alkyls, halogen substituent group；
Alternatively, R3~R6Middle any two adjacent group is constituted together comprising five yuan including quinoline carbon or hexa-atomic part not
Saturated cyclic structure；
Or R3~R6Middle any two adjacent group constitutes the condensed cyclic structure with quinoline ring conjugation, the condensed cyclic structure together
On allow the hetero atom containing at least one of N, O, S hydridization；
The sulfonic acid source is at least provided with a sulfonic material.
2. the microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides as described in claim 1, it is characterised in that：Institute
The R stated1Phenyl, five-ring heterocycles aryl or hexa-member heterocycle aryl.
3. the microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides as described in claim 1, it is characterised in that：
The R2~R6It is the alkyl of H, C1~C20, the alkoxy of C1~C20, ester group, nitro or halogen alone；
Alternatively, R3~R6Middle any two adjacent group constitutes three~five rings condensed-nuclei aromatics with quinoline ring conjugation together.
4. the microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides according to claim 1, it is characterised in that：
The sulfonic acid source is p-methyl benzenesulfonic acid or lignin sulfonic acid；Preferably lignin sulfonic acid.
5. according to the microwave assisted synthesizing method of Claims 1 to 4 any one of them N- (quinoline -2- bases) aromatic amides,
It is characterized in that：The quality of lignin sulfonic acid is not less than the 10% of Quinoline N-Oxide quality；Preferably 10-30%；It is further excellent
It is selected as 20~30%.
6. according to the microwave assisted synthesizing method of Claims 1 to 4 any one of them N- (quinoline -2- bases) aromatic amides,
It is characterized in that：The molar ratio 1: 5~10 of Quinoline N-Oxide and aromatic nitriles；Preferably 1: 7.5~10.
7. according to the microwave assisted synthesizing method of Claims 1 to 4 any one of them N- (quinoline -2- bases) aromatic amides,
It is characterized in that：The power of microwave is not less than 100W；Preferably 100~300W；Further preferably 150~300W.
8. according to the microwave assisted synthesizing method of Claims 1 to 4 any one of them N- (quinoline -2- bases) aromatic amides,
It is characterized in that：The microwave-assisted reaction time is 15~30 minutes.
9. the microwave assisted synthesizing method of N- (quinoline -2- bases) aromatic amides according to claim 1, it is characterised in that：
Reaction is without additional addition reaction dissolvent.
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| JP2001139550A (en) * | 1999-11-17 | 2001-05-22 | Shionogi & Co Ltd | New use of amide compound |
| CN104447536A (en) * | 2014-10-25 | 2015-03-25 | 大连理工大学 | Preparation method of N-2-quinolyl aryl sulfonamide compounds |
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| JP2001139550A (en) * | 1999-11-17 | 2001-05-22 | Shionogi & Co Ltd | New use of amide compound |
| CN104447536A (en) * | 2014-10-25 | 2015-03-25 | 大连理工大学 | Preparation method of N-2-quinolyl aryl sulfonamide compounds |
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| MICHEL COUTURIER等: "Mild and Direct Conversion of Quinoline N-Oxides to 2-Amidoquinolines with Primary Amides", 《ORGANIC LETTERS》 * |
| VALENTIN A. RASSADIN等: "Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C–H functionalization of pyridine N-oxides", 《GREEN CHEMISTRY》 * |
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| CN110156683A (en) * | 2019-06-26 | 2019-08-23 | 青岛农业大学 | The synthetic method of quinoline type oxide |
| CN110156683B (en) * | 2019-06-26 | 2020-06-26 | 青岛农业大学 | Synthesis method of quinoline oxide |
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