CN107721920B - Synthesis method of quinoline amide compound - Google Patents
Synthesis method of quinoline amide compound Download PDFInfo
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- CN107721920B CN107721920B CN201711051846.8A CN201711051846A CN107721920B CN 107721920 B CN107721920 B CN 107721920B CN 201711051846 A CN201711051846 A CN 201711051846A CN 107721920 B CN107721920 B CN 107721920B
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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
- C07D215/18—Halogen atoms or nitro radicals
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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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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Abstract
The invention discloses a method for synthesizing a quinoline amide compound, which comprises the following steps: under the condition of the existence of a transition metal catalyst and an additive, 8-methylquinoline compounds and isocyanate compounds react in an organic solvent to obtain the quinoline amide compounds. The invention adopts transition metal catalyst Rh (III) to directly catalyze C (sp) for the first time3) The isocyanate is inserted into the H bond, so that the technical problem in the prior art is solved, no atom is wasted in the reaction process, and the economic rate of the atom is greatly improved; all the steps are carried out in one reactor, no separation step is needed in the middle, the method belongs to one-pot reaction, the yield of the reaction is greatly improved, the yield can reach more than 90 percent, and the reaction product is easy to purify.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a quinoline amide compound.
Background
Amide compounds, especially aromatic amide compounds, are a basic raw material for industrial applications, and in addition, they are important intermediates in the synthesis of fine chemicals. As a class of aromatic amide compounds with good activity, the quinoline amide compounds have biological activities of sterilization, disinsection, weeding and the like, and are widely applied to the fields of pesticides and medicines. Therefore, research methods for green synthesis of quinoline amide compounds are continuously reported, and researches on the methods are more and more interesting and make great progress.
Most of the conventional methods for preparing amides require conversion of functional groups, and require pre-activation, pre-functionalization, or use of strong oxidants, and the reaction requires harsh conditions, complicated experimental steps, and high cost. Through continuous innovation and improvement, carboxylic acid and derivatives thereof, alcohol, aldehyde and the like can be used as starting materials, and then the amide compound is synthesized through functional group conversion, but the starting materials have high price, low atom economy and large limitation.
The strategy of transition metal catalyzed C — H bond functionalization is a straightforward and efficient method for building synthetic targets. Rh (III) compounds have good reactivity, selectivity and functional group compatibility, and based on the excellent catalytic activity of Rh (III) compounds, Rh (III) -catalyzed C (sp) has been utilized2) -H bond activation to construct carbon-carbon and carbon-heteroatom bonds. However, Rh (III) catalytically inert C (sp)3) The functionalization of the-H bond is relatively rare and such transformations remain a challenging problem. The C-N pi-bonds of polar and reactive isocyanates can be readily reacted with C (sp) by means of transition metal catalysts, for example Re (I), Rh (III), Ru (II), Co (III)2) -H bonds are combined, thereby forming an amide. To the best of our knowledge, C (sp)3) The reaction of the insertion of the-H bond into the isocyanate has not yet been achieved. Probably because the reaction rates of the two substrates are not coordinated: transition metal activated C (sp)3) The reactivity of the-H bond cleavage is relatively low, whereas isocyanates have a higher reactivity. Thus, direct catalysis of C (sp)3) The insertion of the-H bond into the isocyanate is still a technical problem at present, and no relevant solution is reported so far.
Disclosure of Invention
In view of the prior art, the invention aims to provide a method for synthesizing a quinoline amide compound. The invention releases Rh (III) to catalyze C (sp) under mild conditions3) -H bond amidation reaction system and first synthesisA series of quinoline amide compounds are disclosed. The synthetic method has the advantages of simple steps, easily obtained raw materials, high atom economy and environmental friendliness, and provides supplement for the existing amidation method.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing quinoline amide compounds comprises the following steps:
in the presence of a transition metal catalyst and an additive, reacting an 8-methylquinoline compound shown in a formula I with an isocyanate compound shown in a formula II in an organic solvent to obtain a quinoline amide compound shown in a formula III;
wherein R1 represents H, Me, OMe, F, Cl, Br or CF3(ii) a R2 represents phenyl, substituted phenyl, benzyl, C1-C6 alkyl or C3-C7 cycloalkyl.
Preferably, the substituted phenyl group is a methylphenyl group, a methoxyphenyl group, a halophenyl group or a trifluoromethylphenyl group.
In the above synthesis method, the transition metal catalyst is preferably rh (iii); in one embodiment of the present invention, the transition metal catalyst used is [ Cp × RhCl [ ]2]2. The rhodium catalyst selected by the invention can directly catalyze the insertion of C (sp3) -H bonds into isocyanate, and has better catalytic activity compared with other catalysts and transition metal catalysts (such as metal salts or complexes of ruthenium, copper and the like).
In the above synthesis method, the additive is preferably AgSbF6. According to the invention, various additives are optimally selected in the test process, different silver salts containing different anions are screened, and the result shows that other salts can not improve the reaction, and only when the additive is AgSbF6The yield of the product can be greatly improved.
In the above synthesis method, the organic solvent is preferably Dichloromethane (DCM) or Dichloroethane (DCE). In organic chemistry, most reactions are carried out in solvents, which play a very important role in chemical synthesis reactions, and the reaction effects are very different when different solvents are used in the same reaction. The present invention contemplates a variety of reaction solvents during the course of the experiment, such as: 1, 4-dioxane, DMF, THF, etc. it was found that when different organic solvents were used for the reaction, the yields of the final reaction products differed greatly, with DCE being the best solvent and the highest yield.
In the synthesis method, the reaction temperature is 30-90 ℃, and the reaction time is 12-24 h; preferably, the reaction temperature is 60 ℃ and the reaction time is 24 h. The reaction temperature and time are key factors influencing the yield of reaction products, the conditions of the reaction temperature and time are investigated and optimized, and the result shows that when the reaction temperature is 30-90 ℃ and the reaction time is 12-24h, the yield of the reaction products is higher; when the reaction temperature is 60 ℃ and the reaction time is 24 hours, the optimal yield can be obtained, side reactions are not generated basically, and the purification of reaction products is convenient.
In the synthesis method, the equivalent ratio of the transition metal catalyst, the additive, the 8-methylquinoline compound shown in the formula I and the isocyanate compound shown in the formula II is (0.025-0.05): (0.1-0.2): (1-2): (1-2); preferably, the equivalent ratio of the transition metal catalyst, the additive, the 8-methylquinoline compound shown in the formula I and the isocyanate compound shown in the formula II is 0.05: 0.2: 1: 2.
in the above synthesis method, the 8-methylquinoline compound represented by formula I is preferably any one of the following compounds:
in the above synthesis method, the isocyanate compound represented by formula II is preferably any one of the following compounds:
the synthesis method further comprises the step of separating the obtained quinoline amide compound by column chromatography.
The quinoline amide compound synthesized by the method has an amide structure, so that the quinoline amide compound has important application in the fields of insect killing, mite removal and the like.
The invention has the beneficial effects that:
(1) according to the synthesis method of the quinoline amide compound, all the steps are carried out in one reactor, no separation step is needed in the middle, the method belongs to one-pot reaction, the yield of the reaction is greatly improved, the yield can reach more than 90%, and the reaction product is easy to purify.
(2) The invention adopts transition metal catalyst Rh (III) to directly catalyze C (sp) for the first time3) The isocyanate is inserted into the-H bond, the existing technical problem is solved, no atom is wasted in the reaction process, and the atom economy is greatly improved.
(3) The method has the advantages of mild reaction conditions (reaction at about 60 ℃), short reaction time, easily obtained raw materials required by the synthetic reaction, low toxicity and green and safe synthetic reaction.
Drawings
FIG. 1: example 1 hydrogen profile of the prepared product; FIG. 2: example 1 carbon spectrum of the product prepared.
FIG. 3: example 2 hydrogen profile of the prepared product; FIG. 4: example 2 carbon spectrum of the product prepared.
FIG. 5: example 4 hydrogen profile of the product prepared; FIG. 6: example 4 carbon spectrum of the product prepared.
FIG. 7: example 5 hydrogen profile of the prepared product; FIG. 8: example 5 carbon spectrum of the product prepared.
FIG. 9: example 7 hydrogen profile of the product prepared; FIG. 10: example 7 carbon spectrum of the product prepared.
FIG. 11: hydrogen spectrum of the product prepared in example 8; FIG. 12: example 8 carbon spectrum of the product prepared.
FIG. 13: hydrogen spectrum of the product of example 10; FIG. 14: example 10 carbon spectrum of the product prepared.
FIG. 15: hydrogen spectrum of the product of example 11; FIG. 16: example 11 carbon spectrum of the product prepared.
FIG. 17: example 14 hydrogen profile of the product prepared; FIG. 18: example 14 carbon spectrum of the product prepared.
FIG. 19: example 15 hydrogen profile of the product prepared; FIG. 20: example 15 carbon spectrum of the product prepared.
FIG. 21: hydrogen spectrum of the product of example 17; FIG. 22: example 17 carbon spectrum of the product prepared.
FIG. 23: hydrogen spectrum of the product of example 19; FIG. 24: example 19 carbon spectrum of the product prepared.
FIG. 25: example 20 hydrogen profile of the product prepared; FIG. 26: example 20 carbon spectrum of the product prepared.
FIG. 27 is a schematic view showing: hydrogen spectrum of the product of example 21; FIG. 28: example 21 carbon spectrum of the product prepared.
FIG. 29: hydrogen spectrum of the product of example 22; FIG. 30: example 22 carbon spectrum of the product prepared.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background, C (sp) is activated by a transition metal3) The reactivity of the-H bond cleavage is relatively low, while the isocyanate has a high reactivity, and therefore, due to the incompatibility of the two substrate reactions, C (sp) results3) The reaction of the insertion of-H bonds into isocyanates has not been achieved to date. Based on the method, the invention provides a novel method for synthesizing the quinoline amide compound, which can directly synthesize C (sp)3) The isocyanate is inserted into the-H bond, the atom economy is improved, the synthetic method is simple, and the yield is high.
In the synthesis system of the invention, the catalyst [ Cp + RhCl2]2Additive AgSbF6Quinoline amide compounds and isocyanate compoundsThe proportion of addition, the reaction temperature and the reaction time are an organic whole, and the direct addition of C (sp) is realized by combining the conditions3) -H bond is inserted into isocyanate to form amide bond. Omission or replacement of any of the above synthesis systems, or addition of reaction conditions (e.g., addition of basic KOAc) to the reaction system, reduces the yield of the product.
In one embodiment of the present invention, the synthesis of quinolinamides is given as follows:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline compound shown as formula I and 0.4mmol of isocyanate compound shown as formula II are added into a reaction tube, DCE is used as solvent, and N is added2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, separating by column chromatography to obtain the product quinoline amide compound.
The reaction formula of the synthesis is as follows:
in the present invention, "5 mmol%", "20 mmol%" and the like each represent the percentage of the reaction equivalent of the "8-methylquinoline compound", and examples thereof include: 5 mmol% of [ Cp RhCl2]2Denotes [ Cp + RhCl2]2The addition amount of (b) is 5% of the reaction equivalent of the 8-methylquinoline compound.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention are all conventional in the art and commercially available.
The 8-methylquinoline compounds used in the examples and comparative examples of the invention are all conventional commercial products, or are obtained by using 8-methylquinoline as a starting material and performing conventional substitution reaction.
The isocyanate compounds used in the examples and comparative examples of the present invention are all conventional commercially available products, or are prepared by conventional synthesis methods such as phosgene method, addition method, direct catalysis method, etc.
Example 1:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 4-methylphenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (p-tolyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 77%. The structural characterization of the product is shown in fig. 1 and fig. 2, respectively.
Example 2:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.6mmol of 2-methylphenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (o-tolyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether is 9:100, v/v). The yield was 56%. The structural characterization of the product is shown in fig. 3 and fig. 4, respectively.
Example 3:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 3-methylphenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (m-tolyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 65%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.97(s,1H),9.05(dd,J＝4.2,1.7Hz,1H),8.23(dd,J＝8.3,1.7Hz,1H),7.82–7.76(m,2H),7.55–7.49(m,2H),7.30(s,1H),7.18(d,J＝8.2Hz,1H),7.10(t,J＝7.8Hz,1H),6.81(d,J＝7.4Hz,1H),4.30(s,2H),2.27(s,3H).
13C NMR(101MHz,CDCl3)δ169.50,149.50,146.37,138.72,138.55,137.37,133.85,131.20,128.89,128.62,127.54,127.01,124.31,121.37,119.90,116.35,42.47,21.50.
example 4:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 4-methoxyphenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (4-methoxyphenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluant is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 60%. The structural characterization of the product is shown in fig. 5 and fig. 6, respectively.
Example 5:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (4-fluorophenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100 and v/v). The yield was 84%. The structural characterization of the product is shown in fig. 7 and fig. 8, respectively.
Example 6:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 2-chlorophenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (2-chlorphenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, the eluant is ethyl acetate and petroleum ether is 9:100, v/v). The yield was 58%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.99(s,1H),9.04(dd,J＝4.2,1.7Hz,1H),8.37(dd,J＝8.3,1.4Hz,1H),8.22(dd,J＝8.2,1.7Hz,1H),7.83–7.78(m,2H),7.56–7.52(m,1H),7.50–7.47(m,1H),7.26(dd,J＝8.0,1.4Hz,1H),7.20–7.15(m,1H),6.95–6.90(m,1H),4.39(s,2H).
13C NMR(101MHz,CDCl3)δ169.96,150.24,146.38,137.00,135.66,133.54,130.89,128.98,128.72,127.64,127.42,126.82,123.99,122.34,121.51,121.35,42.28.
example 7:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 3-chlorophenyl isocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (3-chlorphenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, the eluant is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 69%. The structural characterization of the product is shown in fig. 9 and fig. 10, respectively.
Example 8:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF6、0.2mmol8-methylquinoline and 0.4mmol of 4-chlorophenyl isocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (4-chlorphenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, the eluant is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 76%. The structural characterization of the product is shown in fig. 11 and fig. 12, respectively.
Example 9:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 4-bromophenyl isocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (4-bromophenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, the eluent is ethyl acetate and petroleum ether is 13:100, v/v). The yield was 70%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ10.25(s,1H),9.04(dd,J＝4.3,1.7Hz,1H),8.25(dd,J＝8.3,1.7Hz,1H),7.81–7.78(m,2H),7.56–7.51(m,2H),7.35–7.30(m,4H),4.29(s,2H).
13C NMR(101MHz,CDCl3)δ169.56,149.45,146.31,137.74,137.53,133.48,131.73,131.37,128.95,127.69,127.07,121.43,120.82,115.85,42.51.
example 10:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 8-methylquinoline and 0.4mmol of 4- (trifluoromethyl) phenylisocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (4- (trifluoromethyl) phenyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate: petroleum ether: 13:100, v/v). The yield was 91%. The structural characterization of the product is shown in fig. 13 and 14, respectively.
Example 11:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgNTf20.2mmol of 8-methylquinoline and 0.6mmol of butyl isocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product 2- (8-quinolyl) -N- (N-butyl) acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, the eluent is ethyl acetate and petroleum ether is 25:100, v/v). The yield was 56%. The structural characterization of the product is shown in fig. 15 and fig. 16, respectively.
Example 12:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 7, 8-dimethylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (7-methyl) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 9:100, v/v). The yield was 85%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.89(s,1H),9.02(dd,J＝4.2,1.7Hz,1H),8.19(dd,J＝8.2,1.7Hz,1H),7.67(d,J＝8.4Hz,1H),7.47–7.44(m,2H),7.38–7.33(m,2H),6.93–6.87(m,2H),4.37(s,2H),2.74(s,3H).
13C NMR(101MHz,CDCl3)δ169.42,159.96,157.56,149.45,146.61,139.60,137.16,134.78,131.20,130.40,127.16,126.52,120.77,120.69,120.45,115.45,115.23,99.99,37.46,20.83.
example 13:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 6, 8-dimethylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (6-methyl) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 81%.
The structural characterization data of the product are as follows:
1H NMR(600MHz,CDCl3)δ10.16(s,1H),8.95(dd,J＝4.2,1.7Hz,1H),8.14(dd,J＝8.3,1.6Hz,1H),7.65(d,J＝1.5Hz,1H),7.53(s,1H),7.47–7.45(m,1H),7.40–7.36(m,2H),6.93–6.89(m,2H),4.25(s,2H),2.51(s,3H).
13C NMR(101MHz,CDCl3)δ169.50,149.50,146.37,138.72,138.55,137.37,133.85,131.20,128.89,128.62,127.54,127.01,124.31,121.37,119.90,116.35,42.47,21.50.
example 14:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 5, 8-dimethylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (5-methyl) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 90%. The structural characterization of the product is shown in fig. 17 and fig. 18, respectively.
Example 15:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 5-methoxy-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (5-methoxy) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 55%. The structural characterization of the product is shown in fig. 19 and fig. 20, respectively.
Example 16:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 7-fluoro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (7-fluoro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100 v/v). The yield was 48%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.72(s,1H),9.05(dd,J＝4.3,1.7Hz,1H),8.24(dd,J＝8.3,1.7Hz,1H),7.81–7.77(m,1H),7.51–7.48(m,1H),7.44–7.37(m,3H),6.95–6.89(m,2H),4.32(d,J＝1.8Hz,2H).
13C NMR(101MHz,CDCl3)δ168.20,162.30,160.1,159.80,157.69,150.46,147.37,137.33,137.32,134.6,134.59,128.85,128.74,125.78,120.90,120.82,120.65,120.63,118.25,118.09,117.80,117.53,115.52,115.29,33.52.
example 17:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 6-fluoro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Under atmosphereCarrying out reaction at the temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (6-fluoro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 68%. The structural characterization of the product is shown in fig. 21 and 22, respectively.
Example 18:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 5-fluoro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (5-fluoro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 63%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.78(s,1H),9.08(dd,J＝4.2,1.6Hz,1H),8.53(dd,J＝8.4,1.6Hz,1H),7.77–7.73(m,1H),7.60–7.57(m,1H),7.39–7.36(m,2H),7.22(dd,J＝9.2,8.2Hz,1H),6.92(t,J＝8.7Hz,2H),4.24(s,2H).
13C NMR(101MHz,CDCl3)δ169.24,160.12,158.47,157.71,155.93,150.30,146.61,146.58,134.56,134.53,130.75,130.73,130.70,130.64,129.65,129.63,129.60,121.47,121.44,120.94,120.86,119.81,119.64,115.53,115.31,110.59,110.40.
example 19:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 7-chloro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (7-chloro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 57%. The structural characterization of the product is shown in fig. 23 and fig. 24, respectively.
Example 20:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 6-chloro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (6-chloro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 71%. The structural characterization of the product is shown in fig. 25 and 26, respectively.
Example 21:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 5-chloro-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (5-chloro) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 65%. The structural characterization of the product is shown in fig. 27 and 28, respectively.
Example 22:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 5-bromo-8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (5-bromo) quinolyl ] acetamide is obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 13:100, v/v). The yield was 60%. The structural characterization of the product is shown in fig. 29 and fig. 30, respectively.
Example 23:
(1) adding 5 mmol% of [ Cp + RhCl2]220 mmol% AgSbF60.2mmol of 7- (trifluoromethyl) 8-methylquinoline and 0.4mmol of 4-fluorophenylisocyanate in a reaction tube, 2ml of DCE as a solvent in N2Reacting in the atmosphere at the reaction temperature of 60 ℃ for 24 h;
(2) after the reaction is finished, the product N- (4-fluorophenyl) -2- [8- (7-trifluoromethyl) quinolyl ] acetamide can be obtained by column chromatography (the column packing is 300-400-mesh column chromatography silica gel, and the eluent is ethyl acetate and petroleum ether which are 9:100, v/v). The yield was 40%.
The structural characterization data of the product are as follows:
1H NMR(400MHz,CDCl3)δ9.18(s,1H),9.13(dd,J＝4.2,1.7Hz,1H),8.30(dd,J＝8.3,1.7Hz,1H),7.93–7.86(m,2H),7.64–7.61(m,1H),7.40–7.35(m,2H),6.96–6.90(m,2H),4.60(d,J＝0.8Hz,2H).
13C NMR(101MHz,CDCl3)δ167.52,157.79,150.82,146.51,137.24,134.41,134.38,133.83,130.45,129.97,127.98,125.42,123.33,123.28,123.09,122.69,121.12,121.04,115.53,115.31,36.88.
comparative example 1:
the product was prepared in the same manner as in example 1 except that the reaction solvent in example 1 was adjusted to DCM, and the yield of the product was calculated to be 72%.
Comparative example 2:
the product was prepared in the same manner as in example 1 except that the reaction solvent in example 1 was adjusted to THF, and the calculated yield of the product was 32%.
Comparative example 3:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The amount of addition of (2) was adjusted to "2".The product was prepared in the same manner as in example 1 except that 5 mmol% "was added and the additive" AgSbF6 "was adjusted to" 10 mmol% ", and the yield of the product was calculated to be 60%.
Comparative example 4:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The product was prepared in the same manner as in example 1 except that the addition amount of (A) was adjusted to "2.5 mmol%", the additive "AgSbF 6" was replaced with "AgPF 6", and the addition amount was adjusted to "10 mmol%", and the yield of the product was calculated to be 22%.
Comparative example 5:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The product was prepared in the same manner as in example 1 except that the addition amount of (A) was adjusted to "2.5 mmol%", the additive "AgSbF 6" was replaced with "AgBF 4", and the addition amount was adjusted to "10 mmol%", and the yield of the product was calculated to be 15%.
Comparative example 6:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The product was prepared in the same manner as in example 1 except that the addition amount of (A) was adjusted to "2.5 mmol%", the addition amount of the additive "AgSbF 6" was adjusted to "10 mmol%", the reaction temperature was adjusted to 100 ℃, and the yield of the product was calculated to be 48%.
Comparative example 7:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The product was prepared in the same manner as in example 1 except that the addition amount of (A) was adjusted to "2.5 mmol%", the addition amount of the additive "AgSbF 6" was adjusted to "10 mmol%", the reaction temperature was adjusted to 30 ℃, and the yield of the product was calculated to be 52%.
Comparative example 8:
the catalyst [ Cp + RhCl ] in example 1 was reacted2]2The product was prepared in the same manner as in example 1 except that the amount of addition of (1) was adjusted to "2.5 mmol%", the amount of addition of the additive "AgSbF 6" was adjusted to "10 mmol%", and further 5 mmol% KOAc was added, and the product was obtained in a calculated yield of 18%.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (6)
1. A method for synthesizing a quinoline amide compound is characterized by comprising the following steps:
in a transition metal catalyst [ Cp RhCl2]2And additive AgSbF6Adding 8-methylquinoline compounds shown in formula I and isocyanate compounds shown in formula II into an organic solvent in the presence of N2Reacting under the atmosphere to obtain the quinoline amide compound shown in the formula III;
wherein R1 represents H, Me, OMe, F, Cl, Br or CF3(ii) a R2 represents phenyl, substituted phenyl, benzyl, C1-C6 alkyl or C3-C7 cycloalkyl;
the organic solvent is dichloromethane or dichloroethane;
the reaction temperature is 60 ℃ and the reaction time is 24 h.
2. The synthesis method according to claim 1, wherein the transition metal catalyst, the additive, the 8-methylquinoline compound represented by the formula I and the isocyanate compound represented by the formula II are added in an equivalent ratio of (0.025-0.05): (0.1-0.2): (1-2): (1-2).
3. The synthesis method according to claim 2, wherein the equivalent ratio of the transition metal catalyst, the additive, the 8-methylquinoline compound represented by the formula I and the isocyanate compound represented by the formula II is 0.05: 0.2: 1: 2.
4. the synthesis method according to claim 1, wherein the 8-methylquinoline compound shown in formula I is any one of the following compounds:
5. the synthesis method according to claim 1, wherein the isocyanate compound represented by formula II is any one of the following compounds:
6. the synthesis method according to claim 1, further comprising the step of subjecting the obtained quinoline amide compound to column chromatography.
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Non-Patent Citations (3)
| Title |
|---|
| "Rhodium(III)-Catalyzed Alkenylation Reactions of 8-Methylquinolines with Alkynes by C(sp3)_H Activation;Bingxian Liu，等;《Angew. Chem. Int. Ed.》;20140312;第53卷;第4191-4195页 * |
| Mild Acylation of C(sp3)−H and C(sp2)−H Bonds under Redox-Neutral Rh(III) Catalysis;Songjie Yu,等;《ACS Catal》;20161013;第6卷;第7744-7748页 * |
| Rhodium(III)-Catalyzed Intermolecular Amidation with Azides via C(sp3)−H Functionalization;Nuancheng Wang，等;《J. Org. Chem》;20150507;第79卷;第5379-5385页 * |
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