CN107721920A - A kind of synthetic method of quinoline amide compound - Google Patents
A kind of synthetic method of quinoline amide compound Download PDFInfo
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- CN107721920A CN107721920A CN201711051846.8A CN201711051846A CN107721920A CN 107721920 A CN107721920 A CN 107721920A CN 201711051846 A CN201711051846 A CN 201711051846A CN 107721920 A CN107721920 A CN 107721920A
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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 kind of synthetic method of quinoline amide compound, comprise the steps：Under the conditions of existing for transition-metal catalyst and additive, 8 methylquinoline class compounds and isocyanate ester compound are reacted in organic solvent, obtain the quinoline amide compound.The present invention is directly catalyzed C (sp using transition-metal catalyst Rh (III) first3) H keys insertion isocyanates, solve existing technical barrier, the waste of course of reaction neither one atom, greatly improve the economy rate of atom；And all steps are carried out in a reactor, centre does not need separating step, belongs to one pot reaction, greatly improves the yield of reaction, yield reaches as high as more than 90%, and reaction product is easy to purify.
Description
Technical field
The present invention relates to technical field of organic synthesis, and in particular to a kind of synthetic method of quinoline amide compound.
Background technology
Amides compound, especially aromatic amides, it is a kind of base stock in commercial Application, in addition, it
And synthesis fine chemicals in important intermediate.Quinoline amide compound is as a kind of fragrance with preferably activity
Amide compound, there is the bioactivity such as sterilization, desinsection and weeding, be all widely used in agricultural chemicals and field of medicaments.Therefore,
The research method of green syt quinoline amide compound is constantly reported, and the research on this respect also increasingly causes people
Interest, also achieve major progress.
The conventional method for preparing acid amides is largely required for the conversion of functional group, and needs pre-activate, pre- functionalization,
Or using strong oxidizer, the condition for reacting required is harsh, and experimental procedure is complicated, and cost is higher.The method of synthesizing amide is passed through
Constantly innovation and improve, can also be by the use of carboxylic acid and its derivative, alcohol, aldehyde etc. as initiation material, then the conversion through functional group
Carry out synthesizing amide compound, but the price of these initiation materials is high, and Atom economy is relatively low, and limitation is bigger.
The strategy of transition metal-catalyzed c h bond functionalization is the direct and effective method for building synthesis target.Rh
(III) class compound has good reactivity, selectivity and functional group compatibility, excellent based on Rh (III) class compound
Catalytic activity existing many utilize Rh (III)-catalysis C (sp2)-H bond activations build carbon-carbon bond and carbon-heteroatom bond
Report.However, Rh (III) catalytically inactive C (sp3)-H key functionalizations research it is relatively fewer, it is this kind of conversion be still one tool
The problem of challenging.Using transition-metal catalyst, for example, Re (I), Rh (III), Ru (II), Co (III), can hold very much
C-N π-the key and C (sp of easy isocyanates making to have polarity and active2)-H bond conjunctions, so as to form acid amides.And according to me
Known C (sp3)-H keys insertion isocyanates reaction still without being implemented.It is probably the reaction rate because the two substrates
It is uncoordinated：Transition metal activation C (sp3) fracture of-H keys it is reactive relatively low, and isocyanates has higher reaction work
Property.Therefore, C (sp are directly catalyzed3)-H keys insertion isocyanates be still current technology problem, so far there are no related solution party
The report of case.
The content of the invention
For above-mentioned prior art, it is an object of the invention to provide a kind of synthetic method of quinoline amide compound.This
Invention have developed Rh (III) catalysis C (sp in a mild condition3)-H key amidation process systems, and a system has been synthesized first
Row quinoline amide compound.The synthetic method step is simple, raw material is easy to get, Atom economy is high, environment-friendly, is existing
Amidation method provides supplement.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of synthetic method of quinoline amide compound, comprises the steps：
Under the conditions of existing for transition-metal catalyst and additive, 8- methylquinoline class compounds and formula shown in Formulas I
Isocyanate ester compound shown in II is reacted in organic solvent, obtains quinoline amide compound described in formula III；
Wherein, R1 represents H, Me, OMe, F, Cl, Br or CF3；R2 represents phenyl, substituted-phenyl, benzyl, C1-C6 alkyl
Or C3-C7 cycloalkyl.
Preferably, the substituted-phenyl is aminomethyl phenyl, methoxyphenyl, halogenophenyl or trifluoromethyl.
In above-mentioned synthetic method, the transition-metal catalyst is preferably Rh (III)；In the specific implementation of the present invention
In mode, used transition-metal catalyst is [Cp*RhCl2]2.Rhodium catalyst selected by the present invention can directly be catalyzed C
(sp3)-H keys insertion isocyanates, with other catalyst and transition-metal catalyst (such as ruthenium, copper metal salt or complexing
Thing) compare, there is more preferable catalytic activity.
In above-mentioned synthetic method, the additive is preferably AgSbF6.The present invention enters in experiment process to multiple additives
Optimum choice is gone, the different silver salt containing different anions is screened, as a result found, other salts can not improve
Reaction, only when additive is AgSbF6Shi Caineng greatly improves the yield of product.
In above-mentioned synthetic method, the organic solvent is preferably dichloromethane (DCM) or dichloroethanes (DCE).Organic
In chemistry, most reaction is carried out in a solvent, and solvent plays very important effect in chemosynthesis reaction, together
Different solvents is used in one reaction, reaction effect is very different.The present invention has attempted a variety of reaction dissolvents during experiment,
Such as：Isosorbide-5-Nitrae-dioxane, DMF, THF etc., as a result have found, are reacted using different organic solvents, final reacting product
Yield difference is very big, and effect is best during using DCE as solvent, the yield highest of its product.
In above-mentioned synthetic method, the temperature of reaction is 30-90 DEG C, and the time of reaction is 12-24h；Preferably, the temperature of reaction
Spend for 60 DEG C, the time of reaction is 24h.The temperature and time of reaction is the key factor for influenceing reaction product yield, of the invention
The temperature and time condition of reaction has been carried out investigating optimization, as a result found, using reaction temperature as 30-90 DEG C, the reaction time is
During 12-24h, the yield of reaction product is higher；When reaction temperature be 60 DEG C, when the time of reaction is 24h, can obtain optimal
Yield, and the generation without side reaction substantially, are easy to the purifying of reaction product.
In above-mentioned synthetic method, transition-metal catalyst, additive, 8- methylquinoline class compounds and formula shown in Formulas I
The equivalent proportion that isocyanate ester compound shown in II adds is (0.025-0.05)：(0.1-0.2)：(1-2)：(1-2)；It is preferred that
, the transition-metal catalyst, additive, the isocyanates shown in 8- methylquinoline class compounds and Formula II shown in Formulas I
The equivalent proportion that class compound adds is 0.05：0.2：1：2.
In above-mentioned synthetic method, the 8- methylquinoline class compounds shown in Formulas I are preferably any of following compound：
In above-mentioned synthetic method, the isocyanate ester compound shown in Formula II is preferably any of following compound：
In above-mentioned synthetic method, in addition to by obtained quinoline amide compound carry out pillar layer separation the step of.
The above method synthesizes obtained quinoline amide compound, because it has amide structure, therefore, in desinsection, removes
The fields such as mite have important purposes.
Beneficial effects of the present invention：
(1) synthetic method of quinoline amide compound of the invention, its all step are carried out in a reactor,
Centre does not need separating step, belongs to one pot reaction, greatly improves the yield of reaction, and yield reaches as high as more than 90%, and
And reaction product is easy to purify.
(2) present invention is directly catalyzed C (sp using transition-metal catalyst Rh (III) first3)-H keys insertion isocyanates,
Solve existing technical barrier, the waste of course of reaction neither one atom, greatly improve the economy of atom.
(3) reaction condition of the invention gentle (being reacted at 60 DEG C or so), reaction time are short, needed for synthetic reaction
Raw material is easy to get, small toxicity, and synthetic reaction is green safe.
Brief description of the drawings
Fig. 1：Embodiment 1 prepares the hydrogen spectrogram of product；Fig. 2：Embodiment 1 prepares the carbon spectrogram of product.
Fig. 3：Embodiment 2 prepares the hydrogen spectrogram of product；Fig. 4：Embodiment 2 prepares the carbon spectrogram of product.
Fig. 5：Embodiment 4 prepares the hydrogen spectrogram of product；Fig. 6：Embodiment 4 prepares the carbon spectrogram of product.
Fig. 7：Embodiment 5 prepares the hydrogen spectrogram of product；Fig. 8：Embodiment 5 prepares the carbon spectrogram of product.
Fig. 9：Embodiment 7 prepares the hydrogen spectrogram of product；Figure 10：Embodiment 7 prepares the carbon spectrogram of product.
Figure 11：Embodiment 8 prepares the hydrogen spectrogram of product；Figure 12：Embodiment 8 prepares the carbon spectrogram of product.
Figure 13：Embodiment 10 prepares the hydrogen spectrogram of product；Figure 14：Embodiment 10 prepares the carbon spectrogram of product.
Figure 15：Embodiment 11 prepares the hydrogen spectrogram of product；Figure 16：Embodiment 11 prepares the carbon spectrogram of product.
Figure 17：Embodiment 14 prepares the hydrogen spectrogram of product；Figure 18：Embodiment 14 prepares the carbon spectrogram of product.
Figure 19：Embodiment 15 prepares the hydrogen spectrogram of product；Figure 20：Embodiment 15 prepares the carbon spectrogram of product.
Figure 21：Embodiment 17 prepares the hydrogen spectrogram of product；Figure 22：Embodiment 17 prepares the carbon spectrogram of product.
Figure 23：Embodiment 19 prepares the hydrogen spectrogram of product；Figure 24：Embodiment 19 prepares the carbon spectrogram of product.
Figure 25：Embodiment 20 prepares the hydrogen spectrogram of product；Figure 26：Embodiment 20 prepares the carbon spectrogram of product.
Figure 27：Embodiment 21 prepares the hydrogen spectrogram of product；Figure 28：Embodiment 21 prepares the carbon spectrogram of product.
Figure 29：Embodiment 22 prepares the hydrogen spectrogram of product；Figure 30：Embodiment 22 prepares the carbon spectrogram of product.
Embodiment
It is noted that described further below is all exemplary, it is intended to provides further instruction to the application.It is unless another
Indicate, all technologies used herein and scientific terminology are with usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
As background technology is introduced, due to transition metal activation C (sp3)-H keys fracture it is reactive relatively low,
And isocyanates has higher reactivity, therefore, because the reaction of the two substrates is uncoordinated, cause C (sp3)-H keys insert
Enter the reaction of isocyanates so far still without being implemented.Based on this, the invention provides a kind of new quinoline amide compound
Synthetic method, the synthetic method can be directly by C (sp3)-H keys insertion isocyanates, improve Atom economy, synthesis side
Method is simple and yield is high.
In the synthetic system of the present invention, catalyst [Cp*RhCl2]2, additive A gSbF6, quinoline amide compound and different
Ratio, reaction temperature and the reaction time that cyanate compound adds are an organic wholes, pass through the knot of above-mentioned condition
Close, realize C (sp directly3)-H keys insertion isocyanates, form amido link.By any condition in above-mentioned synthetic system
It is omitted or substituted, or increases reaction condition (KOAc as added alkalescence) on the basis of reaction system, can all reduces product
Yield.
In one embodiment of the present invention, the synthetic method of the quinoline amide provided is as follows：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 8- methylquinolines shown in 0.2mmol Formulas I
Isocyanate ester compound shown in class compound and 0.4mmol Formula II adds DCE as solvent, in N in reaction tube2
Reacted under atmosphere, reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, product quinoline amide compound is obtained by pillar layer separation.
The reaction equation of synthesis is as follows：
In the present invention, " 5mmol% ", " 20mmol% " etc. represent to account for " 8- methylquinoline classes compound " reaction equivalent
Percentage, such as：5mmol% [Cp*RhCl2]2, represent [Cp*RhCl2]2Addition for 8- methylquinoline class compounds it is anti-
Should measure 5%.
In order that the technical scheme of the application can clearly be understood by obtaining those skilled in the art, below with reference to tool
The embodiment of body describes the technical scheme of the application in detail.
Test material used is the conventional test material in this area in the embodiment of the present invention, can pass through commercial channel
It is commercially available.
Used 8- methylquinoline class compounds are conventional commercially available prod in the embodiment of the present invention and comparative example, or
Using 8- methylquinolines as initiation material, the substitution reaction through routine obtains person.
Isocyanate ester compound used is conventional commercially available prod in the embodiment of the present invention and comparative example, Huo Zhejing
The synthetic methods such as conventional phosgenation, addition process, direct catalysis method are prepared.
Embodiment 1：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- methylphenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere,
Reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (p-methylphenyl) acetamide.
Yield is 77%.The structural characterization difference of product is as depicted in figs. 1 and 2.
Embodiment 2：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.6mmol 2- methylphenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere,
Reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=9:100, v/v), you can obtain product 2- (8- quinolyls)-N- (o-tolyl) acetamide.Production
Rate is 56%.The structural characterization difference of product is as shown in Figure 3 and Figure 4.
Embodiment 3：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 3- methylphenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere,
Reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (tolyl) acetamide.
Yield is 65%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.97 (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.
Embodiment 4：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- methoxyphenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Carried out under atmosphere anti-
Should, reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (4- methoxyphenyls) acetyl
Amine.Yield is 60%.The structural characterization difference of product is as shown in Figure 5 and Figure 6.
Embodiment 5：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (4- fluorophenyls) acetamide.
Yield is 84%.The structural characterization difference of product is as shown in Figure 7 and Figure 8.
Embodiment 6：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 2- chlorophenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=9:100, v/v), you can obtain product 2- (8- quinolyls)-N- (2- chlorphenyls) acetamide.Production
Rate is 58%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.99 (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.
Embodiment 7：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 3- chlorophenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (3- chlorphenyls) acetamide.
Yield is 69%.The structural characterization difference of product is as shown in Figure 9 and Figure 10.
Embodiment 8：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- chlorophenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (4- chlorphenyls) acetamide.
Yield is 76%.The structural characterization difference of product is as is illustrated by figs. 11 and 12.
Embodiment 9：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- bromophenyl isocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (4- bromophenyls) acetamide.
Yield is 70%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 10.25 (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.
Embodiment 10：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 8- methylquinolines and
0.4mmol 4- (trifluoromethyl) phenyl isocyanate adds 2ml DCE as solvent, in N in reaction tube2Enter under atmosphere
Row reaction, reaction temperature are 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product 2- (8- quinolyls)-N- (4- (trifluoromethyl) phenyl)
Acetamide.Yield is 91%.The structural characterization difference of product is as shown in Figure 13 and Figure 14.
Embodiment 11：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgNTf2, 0.2mmol 8- methylquinolines and
0.6mmol butyl isocyanate adds 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, reaction temperature
For 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=25:100, v/v), you can obtain product 2- (8- quinolyls)-N- (normal-butyl) acetamide.Production
Rate is 56%.The structural characterization difference of product is as shown in Figure 15 and Figure 16.
Embodiment 12：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 7,8- dimethyl quinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=9:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (7- methyl) quinolyl]
Acetamide.Yield is 85%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.89 (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.
Embodiment 13：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 6,8- dimethyl quinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (6- methyl) quinolyl]
Acetamide.Yield is 81%.
The structural characterization data of product are as follows：
1H NMR(600MHz,CDCl3) δ 10.16 (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.
Embodiment 14：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 5,8- dimethyl quinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (5- methyl) quinolyl]
Acetamide.Yield is 90%.The structural characterization difference of product is as shown in Figure 17 and Figure 18.
Embodiment 15：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 5- methoxyl group 8- methylquinolines
4- fluorophenylisocyanates with 0.4mmol add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere,
Reaction temperature is 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (5- methoxyl groups) quinoline
Base] acetamide.Yield is 55%.The structural characterization difference of product is as illustrated in figures 19 and 20.
Embodiment 16：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 7- fluorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (7- fluorine) quinolyl] second
Acid amides.Yield is 48%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.72 (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.
Embodiment 17：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 6- fluorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (6- fluorine) quinolyl] second
Acid amides.Yield is 68%.The structural characterization difference of product is as shown in figure 21 and figure.
Embodiment 18：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 5- fluorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (5- fluorine) quinolyl] second
Acid amides.Yield is 63%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.78 (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.
Embodiment 19：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 7- chlorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (7- chlorine) quinolyl] second
Acid amides.Yield is 57%.The structural characterization difference of product is as shown in figure 23 and figure 24.
Embodiment 20：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 6- chlorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (6- chlorine) quinolyl] second
Acid amides.Yield is 71%.The structural characterization difference of product is as illustrated in figs. 25 and 26.
Embodiment 21：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 5- chlorine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (5- chlorine) quinolyl] second
Acid amides.Yield is 65%.The structural characterization of product is respectively as shown in Figure 27 and Figure 28.
Embodiment 22：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 5- bromine 8- methylquinolines and
0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Reacted under atmosphere, instead
It is 60 DEG C to answer temperature, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=13:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (5- bromines) quinolyl] second
Acid amides.Yield is 60%.The structural characterization difference of product is as shown in Figure 29 and Figure 30.
Embodiment 23：
(1) by 5mmol% [Cp*RhCl2]2, 20mmol% AgSbF6, 0.2mmol 7- (trifluoromethyl) 8- methyl
Quinoline and 0.4mmol 4- fluorophenylisocyanates add 2ml DCE as solvent, in N in reaction tube2Carried out under atmosphere
Reaction, reaction temperature are 60 DEG C, reaction time 24h；
(2) after reaction terminates, by pillar layer separation, (chromatographic column filler is 300-400 mesh column layer chromatography silicone rubbers, eluant, eluent
For：Ethyl acetate：Petroleum ether=9:100, v/v), you can obtain product N- (4- fluorophenyls) -2- [8- (7- trifluoromethyls) quinoline
Base] acetamide.Yield is 40%.
The structural characterization data of product are as follows：
1H NMR(400MHz,CDCl3) δ 9.18 (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：
Reaction dissolvent in embodiment 1 is adjusted to DCM, remaining is prepared product, be computed with embodiment 1, product
Yield be 72%.
Comparative example 2：
Reaction dissolvent in embodiment 1 is adjusted to THF, remaining is prepared product, be computed with embodiment 1, product
Yield be 32%.
Comparative example 3：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Addition be adjusted to " 10mmol% ", remaining is prepared product, is computed with embodiment 1, and the yield of product is 60%.
Comparative example 4：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Replace with " AgPF6 ", addition is adjusted to " 10mmol% ", and remaining is prepared product, be computed with embodiment 1, product
Yield is 22%.
Comparative example 5：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Replace with " AgBF4 ", addition is adjusted to " 10mmol% ", and remaining is prepared product, be computed with embodiment 1, product
Yield is 15%.
Comparative example 6：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Addition be adjusted to " 10mmol% ", reaction temperature is adjusted to 100 DEG C, and product is prepared with embodiment 1 in remaining, through meter
Calculate, the yield of product is 48%.
Comparative example 7：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Addition be adjusted to " 10mmol% ", reaction temperature is adjusted to 30 DEG C, and product is prepared with embodiment 1 in remaining, through meter
Calculate, the yield of product is 52%.
Comparative example 8：
By the catalyst [Cp*RhCl in embodiment 12]2Addition be adjusted to " 2.5mmol% ", additive " AgSbF6 "
Addition be adjusted to " 10mmol% ", add 5mmol%KOAc again in addition, product is prepared with embodiment 1 in remaining, passes through
Calculate, the yield of product is 18%.
The preferred embodiment of the application is the foregoing is only, is not limited to the application, for the skill of this area
For art personnel, the application can have various modifications and variations.It is all within spirit herein and principle, made any repair
Change, equivalent substitution, improvement etc., should be included within the protection domain of the application.
Claims (10)
1. a kind of synthetic method of quinoline amide compound, it is characterised in that comprise the steps：
Under the conditions of existing for transition-metal catalyst and additive, 8- methylquinoline class compounds and Formula II institute shown in Formulas I
The isocyanate ester compound shown is reacted in organic solvent, obtains quinoline amide compound described in formula III；
Wherein, R1 represents H, Me, OMe, F, Cl, Br or CF3；R2 represents phenyl, substituted-phenyl, benzyl, C1-C6 alkyl or C3-
C7 cycloalkyl.
2. synthetic method according to claim 1, it is characterised in that the transition-metal catalyst is Rh (III).
3. synthetic method according to claim 1, it is characterised in that the additive is AgSbF6。
4. synthetic method according to claim 1, it is characterised in that the organic solvent is dichloromethane or two chloroethenes
Alkane.
5. synthetic method according to claim 1, it is characterised in that the temperature of reaction is 30-90 DEG C, and the time of reaction is
12-24h。
6. synthetic method according to claim 5, it is characterised in that the temperature of reaction is 60 DEG C, and the time of reaction is
24h。
7. synthetic method according to claim 1, it is characterised in that transition-metal catalyst, additive, shown in Formulas I
The equivalent proportion that isocyanate ester compound shown in 8- methylquinoline class compounds and Formula II adds is (0.025-0.05)：
(0.1-0.2)：(1-2)：(1-2)；Preferably, transition-metal catalyst, additive, the 8- methylquinoline class chemical combination shown in Formulas I
The equivalent proportion that isocyanate ester compound shown in thing and Formula II adds is 0.05：0.2：1：2.
8. synthetic method according to claim 1, it is characterised in that the 8- methylquinoline classes compound shown in Formulas I is such as
Any of lower compound：
9. synthetic method according to claim 1, it is characterised in that the isocyanate ester compound shown in Formula II is preferably
Any of following compound：
10. synthetic method according to claim 1, it is characterised in that the synthetic method also includes the quinoline that will be obtained
Amides compound carries out the step of pillar layer separation.
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Non-Patent Citations (3)
| Title |
|---|
| BINGXIAN LIU，等: ""Rhodium(III)-Catalyzed Alkenylation Reactions of 8-Methylquinolines with Alkynes by C(sp3)_H Activation", 《ANGEW. CHEM. INT. ED.》 * |
| NUANCHENG WANG，等: "Rhodium(III)-Catalyzed Intermolecular Amidation with Azides via C(sp3)−H Functionalization", 《J. ORG. CHEM》 * |
| SONGJIE YU,等: "Mild Acylation of C(sp3)−H and C(sp2)−H Bonds under Redox-Neutral Rh(III) Catalysis", 《ACS CATAL》 * |
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