CN114507180A - Methyl-substituted nitrogen heterocycles C (sp)3) Process for dehydroalkenylation of-H bonds - Google Patents

Methyl-substituted nitrogen heterocycles C (sp)3) Process for dehydroalkenylation of-H bonds Download PDF

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CN114507180A
CN114507180A CN202210047559.4A CN202210047559A CN114507180A CN 114507180 A CN114507180 A CN 114507180A CN 202210047559 A CN202210047559 A CN 202210047559A CN 114507180 A CN114507180 A CN 114507180A
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methyl
substituted nitrogen
heterocyclic compound
nitrogen heterocyclic
dehydroalkenylation
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CN114507180B (en
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王玉梅
化红婉
董春萍
李雪颖
周永生
徐晓莉
李剑
王车礼
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Changzhou University
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Abstract

The invention belongs to an organic compound C (sp)3) The field of-H bond alkenylation, in particular to a methyl-substituted nitrogen heterocyclic compound C (sp)3) -dehydroalkenylation of H bonds itself. In the presence of iodine and organic acid, the methyl-substituted azacyclo compound is used as a substrate, benzylamine is used as an additive, and dimethyl sulfoxide is used as a solvent, so that the methyl-substituted azacyclo compound self dehydroalkenylation product can be effectively synthesized, the reagent is cheap and easy to obtain, a metal catalyst is not used, the reaction condition is mild, the operation is simple and convenient, and the yield is up to 90%.

Description

Methyl-substituted nitrogen heterocycles C (sp)3) Process for dehydroalkenylation of-H bonds
Technical Field
The invention belongs to an organic compound C (sp)3) The field of-H bond alkenylation, in particular to a methyl-substituted nitrogen heterocyclic compound C (sp)3) -dehydroalkenylation of H bonds itself.
Background
Azacyclo compounds are present as important structural units in a large number of molecules, drugs, materials and fine chemicals having important biological activities, for example
Figure BDA0003472803360000011
As maternal drugs, the drugs are mainly for the treatment of leishmaniasis and HIV-1 (Fakhfakh, M.A.; Fournet, A.; Prina, E.; Mouscadet, J. -F.; Frank, X.; Hocquemiler, R.; Figade, B.Bioorg. Med. chem.2003,11, 5013-. Methyl-substituted nitrogen heterocycles C (sp)3) The H-bond olefination is considered as a powerful method for forming C ═ C bonds, and the methods reported in the literature at present are mainly: methyl-substituted azaheterocyclic compounds in SeO2(Kaplan, H.J.Am.chem.Soc.1941,63,2654-2655.) or KOtBu/18-Crown-6(Wang, Z.; Zhang, J.; Shi, J.; Wang, H.RSC adv.2019,9, 30139-. E.g. 2-methylquinoline at KOtUnder the Bu/18-Crown-6 system, the autooxidative dehydroalkenylation product is obtained in DMF by taking oxygen as an oxidant. Such reactive atoms are highly economical, but fewer methods are currently reported.
Figure BDA0003472803360000012
Disclosure of Invention
The invention aims to overcome the defects and provide a methyl-substituted nitrogen heterocyclic compound C (sp)3) The method for self-dehydroalkenylation of the-H bond effectively synthesizes a product of self-dehydroalkenylation of the methyl-substituted nitrogen heterocyclic compound by taking the methyl-substituted nitrogen heterocyclic compound as a substrate, benzylamine as an additive and dimethyl sulfoxide as a solvent in the presence of iodine and organic acid.
In order to realize the purpose, the invention is realized by the following technical scheme:
a methyl-substituted azacyclic compound with general formula
Figure BDA0003472803360000021
In the formula:
Figure BDA0003472803360000022
is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is one of-hydrogen, -methoxy, -ethyl, -bromo or-chloro.
The compound can be any one of the following compounds:
Figure BDA0003472803360000023
methyl-substituted nitrogen heterocyclic compound C (sp)3) A process for the preparation of a-H bond autodehydroalkenylation product, said methyl-substituted nitrogen heterocyclic compound C (sp)3) the-H bond self-dehydroalkenylation product is a compound represented by the formula III,
Figure BDA0003472803360000024
in the formula:
Figure BDA0003472803360000025
is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is one of-hydrogen, -methoxy, -ethyl, -bromo or-chloro.
The methyl-substituted nitrogen heterocyclic compound C (sp)3) -a process for dehydroalkenylation of H bonds itself comprising the steps of:
in oxygen atmosphere, mixing the methyl-substituted nitrogen heterocyclic compound shown in the formula I, benzylamine, iodine and organic acid in a dimethyl sulfoxide solvent for reaction, and performing column chromatography after the reaction to obtain the methyl-substituted nitrogen heterocyclic compound C (sp) shown in the formula III3) -H bonds are themselves dehydroalkenylated products.
The methyl-substituted nitrogen heterocyclic compound C (sp) in the preparation method3) The H bond self-dehydroalkenylation product is any one of the following compounds:
Figure BDA0003472803360000031
to further increase the methyl-substituted nitrogen heterocycles C (sp)3) The yield of the H bond self-dehydrogenation alkylation reaction product is obtained, in the preparation method, the dosage of benzylamine is 1.1-2.0 times of the molar ratio of the methyl-substituted nitrogen heterocyclic compound, the dosage of iodine is 1.1-2.0 times of the molar ratio of the methyl-substituted nitrogen heterocyclic compound, and the dosage of the organic acid is 0.5-2.0 times of the molar ratio of the methyl-substituted nitrogen heterocyclic compound. The concentration of the mixed solution of the methyl-substituted azacyclic compound, benzylamine, iodine, 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.
Furthermore, the reaction time is 18-24 hours, and the temperature is 60-100 ℃.
Further, in the column chromatography step in the preparation method, the preferable column-filling solvent is petroleum ether; the eluent is petroleum ether/ethyl acetate; the packing of the column is 300-400 mesh silica gel, and the specification is 2cm in diameter and 30cm in height.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention relates to a methyl-substituted nitrogen heterocyclic compound C (sp)3) The method for dehydrogenating and alkenylating the-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 in the presence of dimethyl sulfoxide solvent to realize methyl-substituted nitrogen heterocyclic compound C (sp)3) The H bond is dehydrogenated and alkenylated to effectively synthesize a series of methyl-substituted nitrogen heterocyclic compounds C (sp)3) -H-bonded alkenylation products. The method has the advantages of simple and easily obtained reagents, mild reaction conditions, simple and convenient operation, no use of metal catalysts, high atom economy and high yield of up to 90 percent.
Detailed Description
The invention is described in more detail below with reference to the following examples:
methyl-substituted nitrogen heterocyclic compound C (sp) of the invention3) -a process for dehydroalkenylation of H bonds itself comprising the steps of: in oxygen atmosphere, mixing methyl-substituted nitrogen heterocyclic compound, benzylamine, iodine and organic acid in dimethyl sulfoxide solvent for reaction to obtain methyl-substituted nitrogen heterocyclic compound C (sp)3) -H bond autodehydroalkenylation product of the formula:
Figure BDA0003472803360000051
in the formula:
Figure BDA0003472803360000052
is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromo or-chloro. Specifically, the structure is any one of the following structures:
Figure BDA0003472803360000053
the methyl-substituted nitrogen heterocyclic compound has the general formula
Figure BDA0003472803360000054
In the formula:
Figure BDA0003472803360000055
the compound is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, R is any one of-hydrogen, -methoxy, -ethyl, -bromine or-chlorine, and specifically can be any one of the following structural formulas:
Figure BDA0003472803360000061
methyl-substituted nitrogen heterocyclic compound C (sp) of the invention3) In the process for dehydroalkenylation of the-H bond itself, the amount of the respective parameters, the reaction time and the reaction temperature are mainly influenced by the methyl-substituted nitrogen heterocyclic compound C (sp)3) The yield of H bond self-dehydroalkenylation product is, for example, when the amount of benzylamine is 1.1 to 2.0 times the molar ratio of the methyl-substituted nitrogen heterocycle, and/or the amount of iodine is 1.1 to 2.0 times the molar ratio of the methyl-substituted nitrogen heterocycle, and/or the amount of organic acid is 0.5 to 2.0 times the molar ratio of the methyl-substituted nitrogen heterocycle, and/or the concentration of the methyl-substituted nitrogen heterocycle, benzylamine, iodine, and the mixed solution of organic acid and the 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 ℃, the nitrogen heterocycle C (sp) is obtained3) The yield of the-H bond self-dehydroalkenylation product is not less than 50 percent, and particularly when the methyl-substituted nitrogen heterocyclic compound is 4-methylquinoline, the yield can reach more than 90 percent.
Preferred embodiments of the present invention will be described in more detail with reference to specific examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified. In the column chromatography step of the following examples, the packing of the column used was 300-400 mesh silica gel having a diameter of 2cm by a height of 30 cm.
Example 1
The 4-methylquinoline self-dehydroalkenylation product shown in the formula III-a is prepared by the following method:
Figure BDA0003472803360000062
the above reaction equation is for the synthesis of the 4-methylquinoline self-dehydroalkenylation product III-a:
4-methylquinoline (73.3g, 0.5mmol), benzylamine (81.1g,0.75mmol), iodine (196.2g, 0.75mmol), a first organic solvent DMSO (2mL) were sequentially added to the reactor, followed by TFA (57.0g, 0.5mmol), immediately plugging, standing for 2 minutes, stirring for 2 minutes, standing until white smoke in the reactor disappeared, attaching an oxygen balloon, naturally heating to 80 ℃ overnight, and adding 100mL of water to the reaction solution to quench the reaction. The remaining iodine was removed with a saturated aqueous solution of sodium thiosulfate, extracted with a third organic solvent, ethyl acetate (3X 30.0mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried and column chromatographed to give 65.4mg, 90% yield of 4-quinolinovinylquinoline as a yellow solid, formula III-a.
The structure confirmation results are as follows:1H NMR(500MHz,CDCl3)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)；13C NMR(125MHz,CDCl3)δ150.4,148.8,142.2,130.4,129.8,129.7,127.1,126.3,123.5,117.9。
the compound synthesized by the structural identification is 4-quinoline vinyl quinoline shown as a target compound III-a.
Example 2
A2, 6-dimethylquinoline self-dehydroalkenylation product as shown in formula III-b is prepared by the following method:
Figure BDA0003472803360000071
the above reaction equation is the synthesis of 2, 6-dimethylquinoline self-dehydroalkenylation product III-b:
2, 6-dimethylquinoline (77.4g, 0.5mmol), benzylamine (81.1g,0.75mmol), iodine (196.2g, 0.75mmol), a first organic solvent DMSO (2mL) were sequentially added to the reactor, followed by TFA (57.0g, 0.5mmol), immediately plugging, standing for 2 minutes, stirring for 2 minutes, standing until the white smoke in the reactor disappeared, attaching an oxygen balloon, naturally heating to 80 ℃ overnight, and adding 100mL of water to the reaction solution to quench the reaction. The remaining iodine was removed with saturated aqueous sodium thiosulfate, the third organic solvent, ethyl acetate (3X 30.0mL), was extracted, the organic phases were combined, 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 formula III-a as a yellow solid, 52% yield.
The structure confirmation results are as follows:1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 by the structural identification is 1, 2-bis (6-methylquinoline-2-yl) ethylene shown as a target compound III-b.
Example 3
The 6-methoxy-2-methylquinoline self-dehydroalkenylation product shown in the formula III-c is prepared by the following method:
Figure BDA0003472803360000081
the above reaction equation is the synthesis of the 6-methoxy-2-methylquinoline self-dehydroalkenylation product:
6-methoxy-2-methylquinoline (86.7g, 0.5mmol), benzylamine (80.6g,0.75mmol), iodine (151.4g, 0.6mmol), a first organic solvent DMSO (2mL) were sequentially added to the reactor, TFA (57.0g, 0.5mmol) was added, a stopper was immediately plugged, the reactor was allowed to stand for 2 minutes, the mixture was stirred for 2 minutes, the reactor was allowed to stand until white smoke in the reactor disappeared, oxygen was added, the reactor was naturally warmed to 80 ℃ overnight, and 100mL of water was added to the reaction solution to quench the reaction. The remaining iodine was removed with a saturated aqueous solution of sodium thiosulfate, extracted with a third organic solvent, ethyl acetate (3X 30.0mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried and column chromatographed to give 42.7mg of 1, 2-bis (6-methoxyquinolin-2-yl) ethylene, 50% yield as a yellow solid, as shown in formula III-c.
The structure confirmation results are as follows:1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 by the structural identification is 1, 2-bis (6-methoxyquinoline-2-yl) ethylene shown as a target compound III-c.
The following are found in the test: the generation of methyl-substituted nitrogen heterocyclic compound C (sp) can be avoided when dimethyl sulfoxide is used as a solvent3) A cross deamination alkenylation reaction between the-H bond and benzylamine. On the basis of example 1, when the solvent dimethyl sulfoxide is replaced by acetonitrile, methanol, dioxane, an ionic liquid, etc., even after process optimization, the methyl-substituted nitrogen heterocyclic compound C (sp)3) The yield of the self-dehydro-alkylation reaction product of the-H bond is lower than 55%, and a cross-deamination-alkylation product between the self-dehydro-alkylation reaction product and benzylamine is generated, specifically: CH (CH)3CN (28% yield of 4-styrylquinoline, 43% yield of 4-quinolinylquinoline), CH3OH (4-styrylquinoline yield 23%, 4-quinolinylquinoline yield 40%), Dioxane (4-styrylquinoline yield 37%, 4-quinolinylquinoline yield 45%), [ BMlM%]BF4(yield of 4-styrylquinoline 45%, yield of 4-quinolinylquinoline 53%), [ BMlM]PF6(4-styrylquinoline yield 44%,yield of 4-quinolinovinylquinoline 34%).
Process optimized methyl substituted nitrogen heterocyclic compound C (sp) when solvent is replaced by toluene3) The incidence of self-dehydroolefination of the-H bond is less than 10%, more of methyl-substituted nitrogen heterocyclic compound C (sp)3) The cross deamination-alkylation reaction between the H bond and benzylamine, such as in comparative example 1 and comparative example 2 (it is to be noted that the reaction temperature, reaction time, and relative amounts of the respective materials have no effect on the relative probability of occurrence of the self-dehydrogenation-alkylation reaction and the cross deamination-alkylation reaction).
Comparative example 1
The preparation method of the cross deamination alkenyl product of 4-methylquinoline and benzylamine shown in the formula IV-a is as follows:
Figure BDA0003472803360000101
the above reaction equation is the synthesis of the cross-deaminated alkenylated product of 4-methylquinoline and benzylamine:
4-methylquinoline (74.0g, 0.5mmol), benzylamine (82.1g,0.75mmol), iodine (158.1g, 0.6mmol), and a second organic solvent PhMe (2mL) were sequentially added to the reactor, followed by TFA (28.5g, 0.25mmol), immediately plugging, standing for 2 minutes, stirring for 2 minutes, standing until white smoke in the reactor disappeared, adding oxygen, naturally raising the temperature to 110 ℃ overnight, and adding 100mL of water to the reaction solution to quench the reaction. The remaining iodine was removed with a saturated aqueous solution of sodium thiosulfate, extracted with a third organic solvent, ethyl acetate (3X 30.0mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried and column chromatographed to give 64.39mg of 4-styrylquinoline of formula IV-a as a white solid, 87% yield.
Comparative example 2
The preparation method of the cross deamination alkenyl product of 4-methylquinoline and benzylamine shown in the formula IV-a is as follows:
Figure BDA0003472803360000102
the above reaction equation is the synthesis of the cross-deaminated alkenylated product of 4-methylquinoline and benzylamine:
4-methylquinoline (72.4g, 0.5mmol), benzylamine (83.5g,0.75mmol), iodine (189.3g, 0.75mmol), a second organic solvent PhMe (2mL) were sequentially added to the reactor, followed by TFA (28.5g, 0.25mmol), immediately plugging, standing for 2 minutes, stirring for 2 minutes, standing until white smoke in the reactor disappeared, adding oxygen, naturally raising the temperature to 100 ℃ overnight, and adding 100mL of water to the reaction solution to quench the reaction. The remaining iodine was removed with a saturated aqueous solution of sodium thiosulfate, extracted with a third organic solvent, ethyl acetate (3X 30.0mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and then subjected to column chromatography to give a white solid, 58.44mg of 4-styrylquinoline represented by formula IV-a, 81% yield.
In addition, the invention also aims at the advantages of benzylamine and the selection of organic acid, and is also verified, and the results are as follows:
the advantages of benzylamine (DMSO is used as a solvent, and the dosage of the benzylamine is 1.5 times of the mole number of the methyl-substituted nitrogen heterocyclic compounds): aniline (4-quinolinylquinoline yield 0%, 4-formylquinoline yield 20%), cyclohexylamine (4-quinolinylquinoline yield 43%), triethylamine (4-quinolinylquinoline yield 16%, 4-formylquinoline yield 42%), benzylamine (4-quinolinylquinoline yield 83%); triethanolamine ([ BMlM)]BF4As a solvent, the yield of 4-quinolinylquinoline was 19%, and the yield of 4-formylquinoline was 10%)
Selecting an organic acid (DMSO is used as a solvent, and the using amount of the organic acid is 1.0 time of the mole number of the methyl-substituted nitrogen heterocyclic compound): acetic acid (4-styrylquinoline yield 13%, 4-quinolinylquinoline yield 21%), phosphoric acid (4-styrylquinoline yield 9%, 4-quinolinylquinoline yield 67%); 2, 4, 6-trihydroxybenzoic acid ([ BMlM)]BF4Is used as solvent, and the dosage is 0.2 times of the mole number of the methyl-substituted nitrogen heterocyclic compound, the yield of the 4-styryl quinoline is 20 percent, and the yield of the 4-quinoline vinyl quinoline is 5 percent).
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not 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 technical principles of the described embodiments, and such modifications and variations should also be considered as within the scope of the present invention.

Claims (10)

1. Methyl-substituted nitrogen heterocyclic compound C (sp)3) -H bond self dehydroalkenylation process characterized in that: the method comprises the following steps: in oxygen atmosphere, mixing methyl-substituted nitrogen heterocyclic compound, benzylamine, iodine and organic acid in dimethyl sulfoxide solvent for reaction to obtain methyl-substituted nitrogen heterocyclic compound C (sp)3) -H bond autodehydroalkenylation product of the formula:
Figure FDA0003472803350000011
in the formula:
Figure FDA0003472803350000012
is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromo or-chloro.
2. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: methyl-substituted nitrogen heterocycles C (sp)3) The H bond self-dehydroalkenylation product is any one of the following compounds:
Figure FDA0003472803350000013
3. the method of dehydroalkenylation of a methyl-substituted nitrogen heterocycle compound C (sp3) -H bond itself according to claim 1, characterized in that: the general formula of the methyl-substituted nitrogen heterocyclic compound is
Figure FDA0003472803350000021
In the formula:
Figure FDA0003472803350000022
is one of quinoline, quinoxaline, pyridine, pyrazine, pyrimidine, benzothiazole and benzoxazole, and R is any one of-hydrogen, -methoxy, -ethyl, -bromo or-chloro.
4. A methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the methyl-substituted azacyclic compound is any one of the following compounds:
Figure FDA0003472803350000023
5. methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the dosage of benzylamine is 1.1-2.0 times of that of the methyl-substituted nitrogen heterocyclic compound in terms of molar ratio.
6. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the dosage of iodine is 1.1-2.0 times of the molar ratio of the methyl-substituted nitrogen heterocyclic compound.
7. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: amount of organic acid usedIs 0.5 to 2.0 times of the molar ratio of the methyl-substituted nitrogen heterocyclic compound.
8. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the concentration of the methyl-substituted azacyclo compound, benzylamine, iodine, and the mixed solution of the organic acid and the first organic solvent is 0.5-0.8 mol/L.
9. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the reaction time is 18-24 hours, and the temperature is 60-100 ℃.
10. Methyl-substituted nitrogen heterocyclic compound C (sp) according to claim 13) -H bond self dehydroalkenylation process characterized in that: the organic acid is trifluoroacetic acid.
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