CN108373448B - Microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide - Google Patents
Microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide Download PDFInfo
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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 the field of organic synthesis, and particularly discloses a microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide, wherein quinoline nitrogen oxide and aromatic nitrile undergo N-amidation reaction at C2 of quinoline nitrogen oxide under the assistance of lignosulfonic acid and microwaves to obtain the N- (quinoline-2-yl) aromatic amide. The method has the advantages of easily obtained raw materials, simple and convenient reaction conditions, mildness, greenness, energy conservation, high reaction selectivity and yield and excellent substrate functional group compatibility; particularly, the lignosulfonic acid is used as an acid catalyst, so that the lignosulfonic acid is easy to recycle and reuse, the reaction cost is reduced, the pollution problem of the traditional protonic acid catalytic reaction is avoided, and the application value is high.
Description
Technical Field
The invention relates to a microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide, in particular to a method for synthesizing N- (quinoline-2-yl) aromatic amide compound through microwave radiation-assisted quinoline nitrogen oxide amidation reaction, belonging to the technical field of organic intermediate synthesis.
Background
N- (quinolin-2-yl) aromatic amides have good pharmacological activities, such as anticancer activity (nat. chem.2017, 9, 1110), antibacterial activity (j.med. chem.2017, 60, 9, 3755), antiallergic activity (j.med. chem.1988, 31, 6, 1098), trinucleotide repeat-stretch mutation inhibitors (bioorg. med. chem.lett.2016, 26, 15, 3761, j.am. chem.soc.2005, 127, 12657), and the like. Meanwhile, the N- (quinoline-2-yl) aromatic amide is also a very good organic synthesis intermediate in the field of organic synthesis. Therefore, the research on the synthetic method of the N- (quinoline-2-yl) aromatic amide is of great significance.
The existing synthesis methods of N- (quinoline-2-yl) aromatic amide are mainly divided into the following three types:
1) arylation of 2-aminoquinoline (j.am. chem. soc.2000, 122, 2172; j.am.chem.soc.2001, 123, 12650; chem.commun.2014, 50, 15094), coupling reaction of 2-haloquinoline with amide (j.org.chem.2005, 70, 8764; RSC adv.2013, 3, 18787), and limited kinds of raw materials of the quinoline derivatives exist in the reaction of the type; the reaction generally requires basic conditions and basic labile functional groups are susceptible.
2) Quinoline nitrogen fluoride salt based amidation reactions (synth. commun.1994, 24, 2387, Tetrahedron lett.2005, 46, 4487; russ. chem. fill., 2016, 65, 2312). The process of the reaction is that under the condition of ultralow temperature, quinoline is fluorided by fluorine gas to obtain a quinoline nitrogen fluorine salt intermediate, and then the intermediate reacts with acetonitrile to obtain N- (quinoline-2-yl) acetamide. The reaction only reports the preparation of N- (quinoline-2-yl) acetamide compound, and the highest yield is only 55%; fluorine gas has the characteristics of high toxicity, high corrosivity, easy explosion and the like, and the application of the method is severely limited.
3) Based on coupling reactions of quinoline nitroxides with amides (j. org. chem., 2009, 74, 1341, org. lett., 2006, 8, 1929).
Although the source of the raw material quinoline nitrogen oxide is easy to obtain, the reaction conditions of the reaction are harsh, volatile and toxic dichloromethane is required to be used as a reaction medium, oxalyl chloride or trifluorosulfonic anhydride and 2-fluoropyridine are also required to be used as an auxiliary agent, so that the reaction cost is increased, and environmental side effects are caused.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an environment-friendly preparation method of N- (quinoline-2-yl) aromatic amide, which can improve the reaction efficiency, reduce the production cost and reduce the discharge of three wastes in the reaction.
In order to realize the technical purpose, the invention provides a microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide, which takes quinoline nitrogen oxide as a reaction substrate, aromatic nitrile as an N-amidation reagent and lignosulfonic acid as a catalyst to carry out N-amidation reaction under the assistance of microwave radiation to obtain the N- (quinoline-2-yl) aromatic amide compound.
The preparation method comprises the steps of preparing quinoline oxynitride with a structure shown in a formula 1 and an expression R1CN aromatic nitrile, under the catalytic action of microwave radiation and a sulfonic acid source, carrying out N-amidation reaction at C2 position of quinoline nitrogen oxide to obtain N- (quinoline-2-yl) aromatic amide with a structural formula of 2;
said R1The aryl or the heterocyclic aryl of C6-C20 or C5-C20, wherein the aryl or the heterocyclic aryl is allowed to contain at least one substituent of C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano;
said R2～R6Independently H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, C1-C20 alkoxy, C5-C20 saturated or partially unsaturated cycloalkyl, C5-C20 saturated or partially unsaturated heterocycloalkyl, C6-C20 aryl, C5-C20 heterocyclic aryl, ester group or halogen;
the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclic alkyl, the aryl and the heterocyclic aryl are allowed to contain at least one substituent of C1-C6 alkoxy, C1-C6 alkyl and halogen;
or, R3～R6Any two adjacent groups together form a five-membered or six-membered partially unsaturated cyclic structure containing a quinoline carbon;
or R3～R6Any two adjacent groups together form a fused ring structure conjugated with the quinoline ring, and the fused ring structure is allowed to contain at least one hybridized heteroatom in N, O, S;
the sulfonic acid source is a material with at least one sulfonic group.
The core of the invention lies in the coordination of the sulfonic acid source and the microwave radiation synthesis method. Researches show that the yield of the product can be obviously improved, the reaction time is shortened and the synthesis efficiency is obviously improved by adopting the sulfonic acid source to be matched with the microwave radiation synthesis of the invention.
In the present invention, the alkyl group having 1 to 20 is a linear or branched hydrocarbon group having the above-mentioned carbon number, and the alkylene group having 2 to 20 is a hydrocarbon group having at least one carbon-carbon double bond, for example, allyl group, propenyl group, etc.; the alkynyl of C2-C20 is a hydrocarbyl group having at least one carbon-carbon triple bond, such as propargyl; the aryl of C6-C10 is, for example, phenyl or a condensed ring group formed by combining a plurality of benzene rings, such as naphthyl.
The saturated or partially unsaturated cycloalkyl group having 5 to 20 carbon atoms may be saturated carbon or partially unsaturated carbon atoms, for example, a five-or six-membered cyclic group.
The saturated or partially unsaturated heterocyclic hydrocarbon group of C5-C20 is, for example, a five-membered or six-membered cyclic group, the carbon constituting the ring may be replaced by a hetero atom hybrid, and the carbon and/or the hetero atom constituting the ring may be saturated carbon or partially unsaturated carbon.
The heterocyclic aryl group of C5-C20 is, for example, a five-or six-membered aromatic group having a heteroatom, such as N, S or O.
Preferably, R is1Is phenyl, five-membered heterocyclic aromatic hydrocarbon group or six-membered heterocyclic aromatic hydrocarbon group. Even more preferably, R is1Is phenyl, furan, thiophene; or phenyl, furan or thiophene substituted by at least one substituent of C1-C3 alkyl, C1-C3 alkoxy and halogen.
Said R2～R6Independently H, C1-C20 alkyl, C1-C20 alkoxy, ester group, nitro or halogen;
or, R3～R6Any two adjacent groups form three-five ring condensed aromatic hydrocarbon conjugated with quinoline ring.
Further preferably, R is2～R6Independently H, C1-C6 alkyl, C1-C6 alkoxy, ester group, nitro or halogen; even more preferably H, methyl, ethyl, methoxy, ethoxy, carbomethoxy, halogen or nitro; further preferably, R is2～R6Wherein 1-2 substituents are methyl, ethyl, methoxy, ethoxy, carbomethoxy, halogen or nitro; most preferably, R2Is H.
Or, R3-R4、R4-R5Or R5-R6Together form a tricyclic fused ring aromatic hydrocarbon conjugated to a quinoline ring.
Preferably, the quinoline nitroxide has the structure of formula 1-A:
in the formula 1-A, R7Is a substituent at any position on the quinoline ring except the 2, 3 positions;
R7h, C1-C6 alkyl, C6-C20 aryl, C1-C6 alkoxy, C2-C6 ester group, nitro or halogen substituent.
The core of the invention lies in the coordination of the sulfonic acid source and the microwave-assisted synthesis method. Researches show that by adopting the sulfonic acid source and matching with the microwave-assisted synthesis method, the yield of the product can be obviously improved, the reaction time is shortened, and the synthesis efficiency is obviously improved.
Preferably, the sulfonic acid source is p-toluenesulfonic acid or lignosulfonic acid; preferably lignosulfonic acid.
The synergistic effect of the lignosulfonic acid and the microwaves is better, and the yield of the product is higher.
Preferably, the mass of the lignosulfonic acid is not less than 10% of the mass of the quinoline oxynitride; preferably 10 to 30%.
More preferably, the mass of the lignosulfonic acid is 20-30% of the mass of the quinoline oxynitride. In this preferred range, the yield of product is higher.
In the present invention, the amount of the aromatic nitrile compound is not less than the theoretical amount for completely reacting the quinoline nitrogen oxide.
Preferably, the molar ratio of the quinoline oxynitride to the aromatic nitrile compound is 1: 5-10.
Further preferably, the mol ratio of the quinoline nitrogen oxide to the aromatic nitrile compound is 1: 7.5-10. At the preferred molar ratio, the yield of the product is further improved, and the yield can be up to more than 92%.
Preferably, the method comprises the following steps: during the reaction, no additional reaction solvent is added.
Preferably, the method comprises the following steps: the power of the microwave is not lower than 100W; preferably 100 to 300W.
More preferably, the power of the microwave is 150 to 300W. The microwave reaction yield is higher in the range. Further studies have found that the power of the microwaves is preferably 150W. Under the preferred power, the reaction moves to the positive direction, and the yield of the target product is obviously improved.
The preferable microwave-assisted reaction time is 15-30 minutes.
The invention discloses a preferable microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide, quinoline oxynitride and aromatic nitrile (R)1CN) under the action of microwave radiation and lignosulfonic acid catalysis, performing N-amidation reaction at C2 position of quinoline nitrogen oxide to obtain N- (quinoline-2-yl) aromatic amide.
The synthetic route is shown in equation 1:
compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the sources of the initial raw materials of the quinoline nitrogen oxide and the aromatic nitrile are wide;
2) cheap lignosulfonic acid is used as a catalyst, so that on one hand, the catalytic activity is high, and the efficiency of the amidation reaction of nitrogen oxides can be improved; on the other hand, the catalyst can be recovered and reused by simple filtration, so that the cost is effectively reduced, and the problem of environmental pollution caused by the use of other protonic acid catalysts is avoided;
3) microwave radiation is used for assisting the reaction, so that the reaction time is shortened, and the reaction yield is improved;
4) the reaction is carried out under the condition of no solvent, so that the production cost is greatly saved, and the environmental pollution is avoided;
5) the reaction has 100% atomic efficiency, no by-product is generated in the reaction, and the pure N- (quinoline-2-yl) aromatic amide can be obtained by recovering the unreacted aromatic nitrile under reduced pressure and then recrystallizing.
Detailed Description
The following specific examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
The mass fraction refers to the mass ratio of a sulfonic acid source (lignosulfonic acid or p-toluenesulfonic acid) to a quinoline nitrogen oxide raw material.
Example 1
Preparation of N- (quinolin-2-yl) benzamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6H)1.45g (10mmol), benzonitrile 7.65mL (7.73g, 75mmol), 20% mass fraction lignosulfonic acid (i.e., lignosulfonic acid is 20% of the mass of quinoline oxynitride), and the resulting mixture was reacted in a microwave stirred reaction apparatus under microwave irradiation with l50W for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.38g of N- (quinoline-2-yl) benzamide with the yield of 96%.
Example 2
Compared with example 1, the main difference is that the reaction is assisted by 100W microwave radiation instead of 150W microwave radiation:
in a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 100W microwave irradiation for 40 minutes. Filtering to recover lignosulfonic acid in the reaction system, recovering unreacted benzonitrile in the reaction system under reduced pressure, and recrystallizing to obtain 1.93g of N- (quinolin-2-yl) benzamide with a yield of 78%.
Example 3
Compared with example 1, the main difference is that the reaction is assisted by replacing 150W of microwave radiation with 300W of microwave radiation:
in a 25mL round-bottom flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 300W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.38g of N- (quinoline-2-yl) benzamide with the yield of 96%.
Example 4
The main difference compared to example 1 is that 20% mass fraction of lignosulfonic acid was replaced with 10% mass fraction of lignosulfonic acid
In a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 10% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering to recover lignosulfonic acid in the reaction system, recovering unreacted benzonitrile in the reaction system under reduced pressure, and recrystallizing to obtain 2.03g of N- (quinoline-2-yl) benzamide with a yield of 82%.
Example 5
The main difference compared to example 1 is that 20% mass fraction of lignosulfonic acid was replaced with 30% mass fraction of lignosulfonic acid
In a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 30% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.38g of N- (quinoline-2-yl) benzamide with the yield of 96%.
Example 6
The main difference compared to example 1 is the replacement of lignosulfonic acid by the p-toluenesulfonic acid reaction:
in a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 2.58g (15mmol) of p-toluenesulfonic acid were sequentially added, and the resulting mixture was reacted with 150W microwave irradiation in a microwave stirring reaction apparatus for 20 minutes. Recovering unreacted benzonitrile in the reaction system under reduced pressure, adding saturated sodium carbonate aqueous solution to neutralize unreacted p-toluenesulfonic acid, extracting and separating liquid by ethyl acetate, collecting an organic phase, removing ethyl acetate under reduced pressure, and recrystallizing to obtain 1.98g of N- (quinoline-2-yl) benzamide with the yield of 80%.
Example 7
The main difference compared to example 1 is that 7.5 times the stoichiometric amount of benzonitrile has been replaced by 5 times the stoichiometric amount of benzonitrile
In a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 5.10mL (5.15g, 50mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 1.26g of N- (quinoline-2-yl) benzamide with the yield of 51 percent.
Example 8
The main difference compared to example 1 is that 7.5 times the stoichiometric amount of benzonitrile is replaced by 10 times the stoichiometric amount of benzonitrile
In a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 10.21mL (10.3g, 100mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 300W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.38g of N- (quinoline-2-yl) benzamide with the yield of 96%.
Comparative example 1
The main difference compared to example 1 is that the microwave radiation assisted reaction is replaced by a stirred reaction at 100 ℃:
in a 25mL round-bottomed flask, 1.45g (10mmol) of quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignin sulfonic acid were sequentially added, and the resulting mixture was stirred at 100 ℃ for reaction for 24 hours. The thin layer chromatography analysis shows that the target product of the near 2- (1H) -quinolinone is generated, and the liquid chromatography normalization analysis shows that the yield of the N- (quinoline-2-yl) benzamide is less than 10 percent.
Comparative example 2
The main difference compared to example 1 is that the acid catalyst according to the invention is not added:
in a 25mL round-bottom flask, 1.45g (10mmol) of quinoline oxynitride and 7.65mL (7.73g, 75mmol) of benzonitrile were added in this order, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 40 minutes. Thin layer chromatography analysis shows that no target product is generated.
Example 9
Preparation of N- (4-methylquinolin-2-yl) benzamide:
in a 25mL round-bottom flask, 1.59g (10mmol) of 4-methylquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.49g of N- (4-methylquinolin-2-yl) benzamide with the yield of 95%.
Example 10
Preparation of N- (6-methylquinolin-2-yl) benzamide:
in a 25mL round-bottom flask, 1.59g (10mmol) of 6-methylquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.49g of N- (6-methylquinolin-2-yl) benzamide with the yield of 95%.
Example 11
Preparation of N- (8-methylquinolin-2-yl) benzamide:
in a 25mL round-bottom flask, 1.59g (10mmol) of 8-methylquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.41g of N- (8-methylquinolin-2-yl) benzamide with the yield of 92%.
Example 12
Preparation of N- (6-methoxyquinolin-2-yl) benzamide:
in a 25mL round-bottomed flask, 1.75g (10mmol) of 6-methoxyquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering to recover lignosulfonic acid in the reaction system, recovering unreacted benzonitrile in the reaction system under reduced pressure, and recrystallizing to obtain 2.67g of N- (6-methoxyquinoline-2-yl) benzamide with a yield of 96%.
Example 13
Preparation of N- (6-phenylquinolin-2-yl) benzamide:
in a 25mL round-bottomed flask, 2.21g (10mmol) of 6-phenylquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 15% by mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted with 150W microwave irradiation in a microwave stirring reaction apparatus for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 3.11g of N- (6-phenylquinolin-2-yl) benzamide with the yield of 96%.
Example 14
Preparation of N- (6-bromoquinolin-2-yl) benzamide:
in a 25mL round-bottom flask, 2.23g (10mmol) of 6-bromoquinoline nitroxide, 7.65mL (7.73g, 75mmol) of benzonitrile, and 20% mass fraction of lignosulfonic acid were sequentially added, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 3.04g of N- (6-bromoquinoline-2-yl) benzamide with the yield of 93%.
Example 15
Preparation of methyl 2-benzamidoquinoline-6-carboxylate:
2.03g (10mmol) of 6-methyl formate quinoline oxynitride, 7.65mL (7.73g, 75mmol) of benzonitrile and 20% mass fraction of lignosulfonic acid were sequentially added to a 25mL round-bottom flask, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted benzonitrile in the reaction system, and recrystallizing to obtain 2.87g of 2-benzamidoquinoline-6-methyl formate with the yield of 94%.
Example 16
Preparation of 2-methyl-N- (quinolin-2-yl) benzamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6H)1.45g (10mmol), 8.88mL (8.78g, 75mmol) of 2-methylbenzonitrile, 20% mass fraction lignosulfonic acid, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted 2-methylbenzonitrile in the reaction system, and recrystallizing to obtain 2.41g of 2-methyl-N- (quinoline-2-yl) benzamide with the yield of 92%.
Example 17
Preparation of 4-methyl-N- (quinolin-2-yl) benzamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6H)1.45g (10mmol), 8.96mL (8.78g, 75mmol) of 4-methylbenzonitrile, 20% mass fraction lignosulfonic acid, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted 4-methylbenzonitrile in the reaction system, and recrystallizing to obtain 2.51g of 4-methyl-N- (quinoline-2-yl) benzamide, wherein the yield is 96%.
Example 18
Preparation of 4-fluoro-N- (quinolin-2-yl) benzamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6Is H)1.45g (10mmol), 9.08g, 75mmol) of 4-fluorobenzonitrile, 20% by massSeveral lignin sulfonic acid, and the obtained mixture is radiated by 150W microwaves in a microwave stirring reaction device for 25 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted 4-fluorobenzonitrile in the reaction system, and recrystallizing to obtain 2.55g of 4-fluoro-N- (quinoline-2-yl) benzamide with the yield of 96%.
Example 19
Preparation of N- (quinolin-2-yl) furan-2-carboxamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6H)1.45g (10mmol), 6.56mL (6.98g, 75mmol) of 2-cyanofuran, 20% mass fraction lignosulfonic acid, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering lignosulfonic acid in the reaction system, decompressing and recovering unreacted 2-cyano furan in the reaction system, and recrystallizing to obtain 2.21g of N- (quinoline-2-yl) furan-2-formamide with the yield of 93%.
Example 20
Preparation of N- (quinolin-2-yl) thiophene-3-carboxamide:
in a 25mL round bottom flask, quinoline nitroxide (in formula 1, R)2～R6H)1.45g (10mmol), 6.82mL (8.18g, 75mmol) of 3-cyanothiophene, 20% mass fraction lignosulfonic acid, and the resulting mixture was reacted in a microwave stirring reaction apparatus with 150W microwave irradiation for 20 minutes. Filtering and recovering the lignosulfonic acid in the reaction system, decompressing and recovering unreacted 3-cyanothiophene in the reaction system, and recrystallizing to obtain 2.38g of N- (quinoline-2-yl) thiophene-3-formamide with the yield of 94 percent.
The above examples and comparative examples show that the N- (quinolin-2-yl) aromatic amide can be obtained with high efficiency and high yield by the technical scheme of the invention.
It was found by the examples and comparative examples 1, 2 that the sulfonic acid source and the microwave assist are critical to the successful preparation of the present invention.
Further research shows that good yield can be obtained under the microwave power of 100-300W (examples 1-3); wherein, the microwave power is controlled to be 150-300W, and the yield of the product can be higher than 90%.
By selecting the type of sulfonic acid source, higher yields can be obtained (examples 1 and 6), wherein the effect of lignosulfonic acid is better, and in addition, controlling the usage amount of lignosulfonic acid helps to further increase the product yield (examples 1, 4, 5), wherein the usage amount is more than 10%, and the product yield can be as high as 90%.
In addition, controlling the ratio of the raw materials can contribute to further obtaining high yield (examples 1, 7, 8).
Claims (5)
1. A microwave-assisted synthesis method of N- (quinoline-2-yl) aromatic amide is characterized by comprising the following steps: the quinoline nitrogen oxide with the structure shown in formula 1 and the expression R1CN aromatic nitrile, under the action of microwave radiation and catalysis of lignosulfonic acid, carrying out N-amidation reaction at C2 position of quinoline nitrogen oxide to obtain N- (quinoline-2-yl) aromatic amide with a structural formula of formula 2;
the mass of the lignosulfonic acid is 20-30% of that of quinoline oxynitride;
the molar ratio of the quinoline nitroxide to the aromatic nitrile is 1: 7.5-10;
the power of the microwave is 150-300W;
said R1Is C6-C20 aryl or C5-C20 heterocyclic aryl, the aryl or heterocyclic aryl is allowed to contain C1-C6 alkyl, C1-C6 alkoxy, halogen and cyanoAt least one substituent of (a);
said R2～R6Independently H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, C1-C20 alkoxy, C5-C20 saturated or partially unsaturated cycloalkyl, C5-C20 saturated or partially unsaturated heterocycloalkyl, C6-C20 aryl, C5-C20 heterocyclic aryl, ester group or halogen;
the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclic alkyl, the aryl and the heterocyclic aryl are allowed to contain at least one substituent of C1-C6 alkoxy, C1-C6 alkyl and halogen;
or, R3～R6Any two adjacent groups together form a five-membered or six-membered partially unsaturated cyclic structure containing a quinoline carbon;
or R3～R6Any two adjacent groups together form a fused ring structure conjugated with the quinoline ring, and the fused ring structure is allowed to contain at least one hybridized heteroatom in N, O, S.
2. The microwave-assisted synthesis of an N- (quinolin-2-yl) aromatic amide according to claim 1, wherein: said R1Is phenyl, five-membered heterocyclic aromatic hydrocarbon group or six-membered heterocyclic aromatic hydrocarbon group.
3. The microwave-assisted synthesis of an N- (quinolin-2-yl) aromatic amide according to claim 1, wherein:
said R2～R6Independently H, C1-C20 alkyl, C1-C20 alkoxy, ester group, nitro or halogen;
or, R3～R6Any two adjacent groups form three-five ring condensed aromatic hydrocarbon conjugated with quinoline ring.
4. The microwave-assisted synthesis method of an N- (quinolin-2-yl) aromatic amide according to any one of claims 1 to 3, wherein: the microwave-assisted reaction time is 15-30 minutes.
5. The microwave-assisted synthesis method of an N- (quinolin-2-yl) aromatic amide according to claim 1, wherein: the reaction does not require additional reaction solvent.
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