CN114507180B - Methyl-substituted azaheterocyclic compound C (sp 3 ) Method for self dehydroalkenylation of H bonds - Google Patents
Methyl-substituted azaheterocyclic compound C (sp 3 ) Method for self dehydroalkenylation of H bonds Download PDFInfo
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Abstract
The invention belongs to an organic compound C (sp 3 ) In the field of alkenyl H bonds, a methyl-substituted azaheterocyclic compound C (sp 3 ) -a method of dehydroalkenylation of the H bond itself. Under the existence of iodine and organic acid, methyl-substituted nitrogen heterocyclic compound is used as substrate, benzylamine is used as additive, dimethyl sulfoxide is used as solvent, and the product of self dehydroalkenylation of methyl-substituted nitrogen heterocyclic compound can be effectively synthesized.
Description
Technical Field
The invention belongs to an organic compound C (sp 3 ) -H-bond alkenylation, more specifically, to a methyl-substituted azaheterocyclic compound C (sp 3 ) -a method of dehydroalkenylation of the H bond itself.
Background
Nitrogen heterocyclic compounds exist as important building blocks in many molecules with important biological activitiesIn pharmaceuticals, materials and fine chemicals, e.g.The drug is mainly a therapeutic for leishmaniasis and HIV-1 (Fakhfakh, M.A.; fournet, A.; prinaE.; mouscadet, J.; frank, X.; hocquiler, R.; figadere, B.bioorg. Med. Chem.2003,11, 5013-5023.). Methyl-substituted azaheterocyclic compound C (sp 3 ) The H-bond alkenylation reaction is considered to be a powerful method of constructing c=c bonds, the methods reported in the literature today are mainly: methyl-substituted azaheterocyclic compounds in SeO 2 (Kaplan, H.J.am.chem.Soc.1941,63, 2654-2655.) or KO t Bu/18-Crown-6 (Wang, Z.; zhang, J.; shi, J.; wang, H.RSC adv.2019,9, 30139-30143.) can effect autooxidative dehydroalkenylation. For example 2-methylquinoline at KO t Under the system of Bu/18-Crown-6, oxygen is taken as an oxidant, and the self oxidative dehydrogenation alkenyl product is obtained in DMF. Such reaction atoms are economical, but few methods are reported.
Disclosure of Invention
The object of the present invention is to provide a methyl-substituted azaheterocyclic compound C (sp 3 ) In the presence of iodine and organic acid, methyl substituted nitrogen heterocyclic compound is used as substrate, benzylamine is used as additive, dimethyl sulfoxide is used as solvent, and the product of the self dehydroalkenylation of methyl substituted nitrogen heterocyclic compound is effectively synthesized.
In order to achieve the above purpose, the invention is realized by the following technical scheme:
methyl-substituted nitrogen heterocyclic compounds of the general formula
Wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine.
The compound can be any one of the following compounds:
methyl-substituted nitrogen heterocyclic compound C (sp 3 ) Process for the preparation of the product of self dehydroalkenylation of the H bond, said methyl-substituted nitrogen heterocyclic compound C (sp 3 ) The H bond itself dehydroalkenylation product is a compound of formula III,
wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine.
The methyl-substituted nitrogen heterocyclic compound C (sp 3 ) A process for the self dehydroalkenylation of H bonds comprising the steps of:
in oxygen atmosphere, mixing methyl-substituted nitrogen heterocyclic compound, benzylamine, iodine and organic acid in dimethyl sulfoxide solvent for reaction, and column chromatography to obtain methyl-substituted nitrogen heterocyclic compound C (sp 3 ) H bond itself dehydroalkenylation product.
Methyl-substituted azaheterocyclic compound C (sp 3 ) The H bond itself dehydroalkenylation product is any of the following compoundsMeaning a:
to further increase the methyl-substituted azacyclic compound C (sp 3 ) The yield of the product of the self dehydroalkenylation reaction of H bond, the benzyl amine is 1.1-2.0 times of the methyl substituted nitrogen heterocyclic compound in terms of mole ratio, the iodine is 1.1-2.0 times of the methyl substituted nitrogen heterocyclic compound in terms of mole ratio, and the organic acid is 0.5-2.0 times of the methyl substituted nitrogen heterocyclic compound in terms of mole ratio. The concentration of the methyl-substituted nitrogen heterocyclic compound, benzylamine, iodine and the mixed solution of the organic acid and the first organic solvent is 0.5-0.8 mol/L.
The organic acid in the above preparation method is preferably trifluoroacetic acid.
Further, the reaction time is 18 to 24 hours, and the temperature is 60 to 100 ℃.
Further, in the above preparation method, in the column chromatography step, the preferred column packing solvent is petroleum ether; the eluent is petroleum ether/ethyl acetate; the column packing used was 300-400 mesh silica gel with a specification of 2cm diameter by 30cm height.
Compared with the prior art, the invention has the beneficial effects that:
(1) A methyl-substituted azaheterocyclic compound C (sp 3 ) The method for self dehydroalkenylation of H bond has the advantages of simple and easily obtained reagent, simple and convenient operation, no use of metal catalyst and high atom economy.
(2) The invention takes methyl-substituted nitrogen heterocyclic compounds with different structures as raw materials, takes benzylamine as an additive in an iodine/organic acid system under a dimethyl sulfoxide solvent to realize methyl-substituted nitrogen heterocyclic compound C (sp 3 ) H bond is self dehydroalkenylated, effectively synthesizing a series of methyl substituted nitrogen heterocyclic compounds C (sp 3 ) -H-bond alkenylation products. The method has the advantages of simple and easily obtained reagent, mild reaction condition, simple operation, no use of metal catalyst, high atom economy and high yieldUp to 90%.
Detailed Description
The invention is further described in detail below in connection with the examples:
methyl-substituted azacyclic compounds C (sp) 3 ) A process for the self dehydroalkenylation of H bonds comprising the steps of: in oxygen atmosphere, methyl substituted nitrogen heterocyclic compound, benzylamine, iodine and organic acid are mixed and reacted in dimethyl sulfoxide solvent to obtain methyl substituted nitrogen heterocyclic compound C (sp 3 ) The H bond itself is dehydroalkenylation product of the formula:
wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine. Specifically, the structure is any one of the following structures:
the general formula of the methyl-substituted nitrogen heterocyclic compound used is
Wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine, and can be specifically any one of the following structural formulas:
methyl-substituted azacyclic compounds C (sp) 3 ) In the process of self-dehydroalkenylation of H bonds, the amount of each parameter, the reaction time and the reaction temperature mainly influence the methyl-substituted nitrogen heterocyclic compound C (sp 3 ) The yield of H bond self-dehydroalkenylation product, for example, when the amount of benzylamine is 1.1 to 2.0 times by mole as compared with the methyl-substituted nitrogen heterocyclic compound, and/or the amount of iodine is 1.1 to 2.0 times by mole as compared with the methyl-substituted nitrogen heterocyclic compound, and/or the amount of organic acid is 0.5 to 2.0 times by mole as compared with the methyl-substituted nitrogen heterocyclic compound, and/or the concentration of methyl-substituted nitrogen heterocyclic compound, benzylamine, iodine and the mixture of organic acid and first organic solvent is 0.5 to 0.8 mol/liter, and/or the reaction time is 18 to 24 hours and the temperature is 60 to 100 ℃, nitrogen heterocyclic compound C (sp 3 ) The yield of the self dehydroalkenylation product of the H bond is not lower than 50%, and especially when the methyl substituted nitrogen heterocyclic compound is 4-methylquinoline, the yield can reach more than 90%.
Preferred embodiments of the present invention will be described in more detail below in connection with specific examples. The methods are conventional methods unless otherwise specified. The starting materials are commercially available from the public unless otherwise specified. In the column chromatography step of the following examples, the column was packed with 300-400 mesh silica gel in a size of 2cm diameter by 30cm height.
Example 1
A4-methylquinoline self-dehydroalkenylation product shown in a formula III-a is prepared by the following steps:
the above reaction equation is for the synthesis of the 4-methylquinoline self dehydroalkenylation product III-a:
4-methylquinoline (73.3 g,0.5 mmol), benzylamine (81.1 g,0.75 mmol), iodine (196.2 g,0.75 mmol), a first organic solvent DMSO (2 mL), then TFA (57.0 g,0.5 mmol) was added sequentially to the reactor, the plug was immediately plugged, allowed to stand for 2 minutes, stirred for 2 minutes, allowed to stand until white fumes in the reactor disappeared, an oxygen balloon was attached, and the temperature was naturally raised to 80℃overnight, and 100mL of water was added to the reaction mixture to quench the reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, and the organic phases were combined by extraction with ethyl acetate (3X 30.0 mL), dried over anhydrous sodium sulfate, filtered, and column chromatographed after spin-drying to give the yellow solid, formula III-a, 4-quinolinylquinoline 65.4mg,90% yield.
The structure validation results are as follows: 1 H NMR(500MHz,CDCl 3 )δ8.98(d,J＝4.5Hz,2H),8.20(d,J＝8.4Hz,2H),8.18(d,J＝8.5Hz,2H),8.01(s,2H),7.78-7.75(m,2H),7.69(d,J＝4.5Hz,2H),7.63-7.60(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ150.4,148.8,142.2,130.4,129.8,129.7,127.1,126.3,123.5,117.9。
the compound synthesized by structural identification is 4-quinoline vinyl quinoline shown as a target compound III-a.
Example 2
A2, 6-dimethylquinoline self-dehydroalkenylation product shown in a formula III-b is prepared by the following steps:
the reaction equation is the synthesis of the self dehydroalkenylation product III-b of 2, 6-dimethylquinoline:
to the reactor was added 2, 6-dimethylquinoline (77.4 g,0.5 mmol), benzylamine (81.1 g,0.75 mmol), iodine (196.2 g,0.75 mmol), first organic solvent DMSO (2 mL), then TFA (57.0 g,0.5 mmol), immediately stoppered, allowed to stand for 2 minutes, stirred for 2 minutes again, allowed to stand until white fumes in the reactor disappeared, oxygen balloon was attached, and naturally warmed to 80℃overnight, and 100mL of water was added to quench the reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, and the organic phases were combined by extraction with ethyl acetate (3X 30.0 mL), dried over anhydrous sodium sulfate, filtered, and column chromatographed after spin-drying to give 39.8mg of 1, 2-bis (6-methylquinolin-2-yl) ethylene of the yellow solid formula III-a, 52% yield.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝8.0Hz,2H),8.00(d,J＝8.6Hz,2H),7.89(s,2H),7.80(d,J＝8.6Hz,2H),7.58-7.55(m,4H),2.55(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ154.8,147.0,136.7,136.0,134.4,132.3,129.2,127.8,126.6,119.6,21.8。
the compound synthesized through structural identification is 1, 2-bis (6-methylquinolin-2-yl) ethylene shown as a target compound III-b.
Example 3
A6-methoxy-2-methylquinoline self-dehydroalkenylation product shown in the formula III-c is prepared by the following steps:
the reaction equation is the synthesis of the self dehydroalkenylation product of 6-methoxy-2-methylquinoline:
6-methoxy-2-methylquinoline (86.7 g,0.5 mmol), benzylamine (80.6 g,0.75 mmol), iodine (151.4 g,0.6 mmol), a first organic solvent DMSO (2 mL), followed by TFA (57.0 g,0.5 mmol), immediately plugging, standing for 2 minutes, stirring for 2 minutes again, standing until white smoke in the reactor disappeared, adding oxygen, naturally heating to 80℃overnight, and adding 100mL of water to the reaction solution for quenching reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, and the organic phases were combined by extraction with ethyl acetate (3X 30.0 mL), dried over anhydrous sodium sulfate, filtered, and column chromatographed after spin-drying to give 42.7mg of 1, 2-bis (6-methoxyquinolin-2-yl) ethylene as a yellow solid of formula III-c, 50% yield.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.6Hz,2H),8.00(d,J＝9.2Hz,2H),7.85(s,2H),7.79(d,J＝8.6Hz,2H),7.38(dd,J＝9.2,2.6Hz,2H),7.09(d,J＝2.6Hz,2H),3.96(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ158.1,153.4,144.5,135.4,133.7,131.0,128.7,122.6,119.9,105.3,55.7。
the compound synthesized through structural identification is 1, 2-bis (6-methoxyquinolin-2-yl) ethylene shown as a target compound III-c.
In the test, it was found that: methyl-substituted azaheterocyclic compound C (sp) can be avoided when dimethyl sulfoxide is used as solvent 3 ) Cross deamination alkenylation reaction between H bond and benzylamine. On the basis of example 1, when dimethyl sulfoxide solvent is replaced with acetonitrile, methanol, dioxane, ionic liquid, etc., even though the process is optimized, methyl-substituted nitrogen heterocyclic compound C (sp 3 ) The self dehydroalkenylation reaction product yields of the H bonds are all lower than 55% and there is the formation of a cross deaminated alkenylation product with benzylamine, in particular: CH (CH) 3 CN (4-styryl quinoline yield 28%, 4-quinolinyl quinoline yield 43%), CH 3 OH (4-styryl quinoline yield 23%, 4-quinolinyl quinoline yield 40%), dioxane (4-styryl quinoline yield 37%, 4-quinolinyl quinoline yield 45%), [ BMlM ]]BF 4 (4-styrylquinoline yield 45%, 4-quinolinylquinoline yield 53%), [ BMlM]PF 6 (4-styryl quinoline yield 44%, 4-quinolinyl quinoline yield 34%).
When the solvent is replaced with toluene, the process-optimized methyl-substituted azaheterocyclic compound C (sp 3 ) The occurrence of self dehydroalkenylation of the H bond is less than 10%, more particularly of methyl-substituted nitrogen heterocyclic compound C (sp 3 ) Cross-deaminated alkenylation between H-bond and benzylamine, such as comparative example 1 and comparative example 2 (it is noted that the reaction temperature, reaction time, and relative amounts of the materials have no effect on the relative probability of occurrence of self-dehydroalkenylation and cross-deaminated alkenylation).
Comparative example 1
A cross deamination alkenyl product of 4-methylquinoline and benzylamine shown in the formula IV-a is prepared by the following steps:
the reaction equation above is the synthesis of the cross deaminated alkenylation product of 4-methylquinoline with benzylamine:
4-methylquinoline (74.0 g,0.5 mmol), benzylamine (82.1 g,0.75 mmol), iodine (158.1 g,0.6 mmol), a second organic solvent PhMe (2 mL) and then TFA (28.5 g,0.25 mmol) were added sequentially to the reactor, the plug was immediately plugged, allowed to stand for 2 minutes, stirred for 2 minutes, allowed to stand until white fumes in the reactor disappeared, oxygen was added, and the temperature was naturally raised to 110℃overnight, and 100mL of water was added to the reaction mixture to quench the reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, and the organic phases were combined by extraction with ethyl acetate (3X 30.0 mL), dried over anhydrous sodium sulfate, filtered, and column chromatographed after spin-drying to give the white solid 4-styrylquinoline 64.39mg,87% yield as shown in formula IV-a.
Comparative example 2
A cross deamination alkenyl product of 4-methylquinoline and benzylamine shown in the formula IV-a is prepared by the following steps:
the reaction equation above is the synthesis of the cross deaminated alkenylation product of 4-methylquinoline with benzylamine:
4-methylquinoline (72.4 g,0.5 mmol), benzylamine (83.5 g,0.75 mmol), iodine (189.3 g,0.75 mmol), a second organic solvent PhMe (2 mL) and then TFA (28.5 g,0.25 mmol) were added sequentially to the reactor, the plug was immediately plugged, allowed to stand for 2 minutes, stirred for 2 minutes, allowed to stand until white fumes in the reactor disappeared, oxygen was added, and the temperature was naturally raised to 100℃overnight, and 100mL of water was added to quench the reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, and the organic phases were combined by extraction with ethyl acetate (3X 30.0 mL), dried over anhydrous sodium sulfate, filtered, and column chromatographed after spin-drying to give the white solid, 58.44mg of 4-styrylquinoline of formula IV-a, 81% yield.
In addition, the invention also verifies the advantages of benzylamine and the selection of organic acid, and the results are as follows:
the advantage of benzylamine (DMSO as solvent and in 1.5 times the molar amount of methyl-substituted aza ring compound): aniline (0% yield of 4-quinolinvinylquinoline, 20% yield of 4-quinolinylquinoline), cyclohexylamine (43% yield of 4-quinolinvinylquinoline), triethylamine (16% yield of 4-quinolinvinylquinoline, 42% yield of 4-quinolinylquinoline), benzylamine (83% yield of 4-quinolinylquinoline); triethanolamine ([ BMlM)]BF 4 As a solvent, the yield of 4-quinoline vinyl quinoline was 19%, and the yield of 4-aldehyde quinoline was 10%)
The organic acid is selected (DMSO is used as a solvent, and the dosage is 1.0 times of the mole number of the methyl substituted nitrogen heterocyclic compound): acetic acid (13% yield of 4-styryl quinoline, 21% yield of 4-quinolinyl quinoline), phosphoric acid (9% yield of 4-styryl quinoline, 67% yield of 4-quinolinyl quinoline); 2,4, 6-Trihydroxybenzoic acid ([ BMlM)]BF 4 Is solvent and the dosage is 0.2 times of mole number of methyl substituted nitrogen heterocyclic compound, the yield of 4-styryl quinoline is 20 percent, and the yield of 4-quinolinyl quinoline is 5 percent).
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described, and these modifications and variations should also be considered as being within the scope of the invention.
Claims (7)
1. Methyl-substituted nitrogen heterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the method comprises the following steps: in oxygen atmosphere, methyl substituted nitrogen heterocyclic compound, benzylamine, iodine and organic acid are mixed and reacted in dimethyl sulfoxide solvent to obtain methyl substituted nitrogen heterocyclic compound C (sp 3 ) The H bond itself is dehydroalkenylation product of the formula:
wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine;
the general formula of the methyl substituted nitrogen heterocyclic compound is
Wherein:is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine;
the organic acid is trifluoroacetic acid.
2. Methyl-substituted azaheterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: methyl-substituted azaheterocyclic compound C (sp 3 ) The H bond itself dehydroalkenylation product is any one of the following compounds:
3. a methyl-substituted nitrogen heterocycle according to claim 1Compound C (sp) 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the methyl-substituted nitrogen heterocyclic compound is any one of the following compounds:
4. methyl-substituted azaheterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the dosage of the benzylamine is 1.1 to 2.0 times of that of the methyl substituted azaheterocyclic compound in terms of molar ratio.
5. Methyl-substituted azaheterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the iodine is used in an amount of 1.1 to 2.0 times by mole of the methyl-substituted azaheterocyclic compound.
6. Methyl-substituted azaheterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the organic acid is used in an amount of 0.5 to 2.0 times by mole of the methyl-substituted azaheterocyclic compound.
7. Methyl-substituted azaheterocyclic compound C (sp 3 ) -a process for the self dehydroalkenylation of H bonds, characterized in that: the reaction time is 18-24 hours, and the temperature is 60-100 ℃.
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