CN111302880B - Application of iron catalyst in reduction coupling reaction and preparation method of aromatic ring and heterocyclic derivative - Google Patents

Application of iron catalyst in reduction coupling reaction and preparation method of aromatic ring and heterocyclic derivative Download PDF

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CN111302880B
CN111302880B CN202010170755.1A CN202010170755A CN111302880B CN 111302880 B CN111302880 B CN 111302880B CN 202010170755 A CN202010170755 A CN 202010170755A CN 111302880 B CN111302880 B CN 111302880B
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iron catalyst
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aromatic ring
naphthalene
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CN111302880A (en
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冯璋
陈硕
蒲宇
周上生
朱江
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North Sichuan Medical College
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    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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Abstract

The invention provides an application of an iron catalyst in reduction coupling reaction of a phenol derivative and an alkyl halide, wherein the iron catalyst is ferrous bromide or ferrous iodide. The invention also provides a preparation method of the aromatic ring and heterocyclic derivative, which adopts the iron catalyst to catalyze the reduction coupling reaction of the phenol derivative and the alkyl halide to prepare the aromatic ring and heterocyclic derivative. The iron catalyst is applied to the reduction coupling reaction of the phenol derivatives and the alkyl halide for the first time, the iron catalyst is low in cost and non-toxic, and the use of the phenol derivatives also reduces the preparation cost; the aromatic ring and heterocyclic ring derivatives are prepared by taking the phenol derivatives and alkyl halides as reactants, taking tetramethylethylenediamine as ligand, taking lithium methoxide as alkali and taking methyl tert-butyl ether as solvent, the preparation process is simple and easy to control, the cost is lower, the yield is higher, the problems of high cost, high toxicity, environment friendliness and the like of the catalyst and reaction raw materials are effectively solved, and the application prospect is wide.

Description

Application of iron catalyst in reduction coupling reaction and preparation method of aromatic ring and heterocyclic derivative
Technical Field
The invention belongs to the technical field of iron catalytic reduction coupling, and particularly relates to application of an iron catalyst in reduction coupling reaction and preparation methods of aromatic ring and heterocyclic derivatives.
Background
The carbon-carbon bond coupling reaction catalyzed by transition metal is a very important reaction in the field of organic synthesis, and provides a high-efficiency tool for synthesizing chemicals such as medicines, materials and the like. At present, the transition metal catalyzed carbon-carbon bond coupling reaction mainly utilizes the traditional suzuki reaction, kumada reaction and the like, and an electrophile (such as a halide, a sulfonate and the like) and a nucleophile (generally a metal reagent such as a magnesium reagent, an organic boride and the like) are required. However, the organometallic reagents required for these reactions are generally expensive and unstable, are harsh to storage conditions, and even require preparation, and the reaction conditions for these reactions are also generally harsh, require no water or oxygen, and impose high operational requirements, limiting the utility of these reactions.
The carbon-carbon bond coupling of two electrophilic reagents is realized by adding a reducing agent into a reaction system in one step, and the reduction coupling reaction catalyzed by transition metal is rapidly developed into the most direct, simple and flexible method for constructing the carbon-carbon bond. However, the research of the reduction coupling reaction at present mainly focuses on the transition metal catalysts such as nickel, palladium, copper and the like, the metal catalysts are expensive or have biotoxicity which influences the later modification of the medicine, and the reduction coupling reaction taking the green and cheap iron as the catalyst has very important significance.
Organic halides are widely used in organic synthesis due to their good reactivity and relatively inexpensive price, but have the disadvantage that the use of large amounts of halogen is harmful to the environment, limiting their application. The phenolic derivatives are compounds widely existing in the nature, are easy to obtain and low in price, and waste generated in the reaction has low harm to the environment, so that the coupling reaction is directly performed by cutting off carbon-oxygen bonds, which attract people's attention, but the carbon-oxygen bonds have stronger energy than carbon-halogen bonds, and transition metals are not easy to directly perform oxidation addition. At present, nickel catalysis is more researched in the direction, and iron-catalyzed reactions for cutting carbon-oxygen bonds are only reported in a small amount and have single reaction types. In addition, in order to perform oxidative addition to the carbon-oxygen bond, an electron-donating ligand (e.g., phosphine ligand, carbene, etc.) is generally required to obtain a metal catalyst having a low valence state, but these ligands are generally expensive and difficult to synthesize.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the application of the iron catalyst in the reduction coupling reaction and the preparation method of the aromatic ring and heterocyclic derivatives, the iron catalyst is applied to the reduction coupling reaction of the phenol derivatives and the alkyl halide for the first time, the iron catalyst has lower cost and no toxicity, and the use of the phenol derivatives also reduces the preparation cost; the aromatic ring and heterocyclic ring derivatives are prepared by taking the phenol derivatives and alkyl halides as reactants, taking tetramethylethylenediamine as ligand, taking lithium methoxide as alkali and taking methyl tert-butyl ether as solvent, the preparation process is simple and easy to control, the cost is lower, the yield is higher, the problems of high cost, high toxicity, environment friendliness and the like of the catalyst and reaction raw materials are effectively solved, and the application prospect is wide.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows: provides an application of an iron catalyst in the reduction coupling reaction of a phenol derivative and an alkyl halide.
Further, the iron catalyst is ferrous bromide or ferrous iodide.
The iron catalyst is adopted to catalyze the reduction coupling reaction of the phenol derivative and the alkyl halide to prepare the aromatic ring and heterocyclic derivative.
A preparation method of aromatic ring and heterocyclic derivatives comprises the following steps:
(1) weighing an iron catalyst, a phenol derivative, lithium methoxide and bis-pinacolato diborate under a sealed and oxygen-free condition to obtain a mixed raw material, connecting the two rows of tubes, and performing nitrogen gas pumping and exchanging for 2-4 times, replacing a rubber plug, and then performing nitrogen gas pumping and exchanging for 2-4 times at an interval of 3-5 min each time; the molar ratio of the iron catalyst to the phenol derivative to the lithium methoxide to the bis-pinacol diboron ester is 0.01-0.03: 0.1-0.3: 1-1.5: 0.4-0.6;
(2) adding a ligand, an alkyl halide and an organic solvent into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting at a constant temperature of 50-90 ℃ for 12-16 h; the molar ratio of the ligand to the alkyl halide to the phenol derivative is 0.01-0.03: 0.2-0.4: 0.1-0.3; the molar volume ratio of the ligand to the organic solvent is 0.01-0.03: 1 mol/L;
(3) and (3) quenching the reaction in the step (2) by using an ammonium chloride saturated solution, and then sequentially carrying out extraction, drying, vacuum concentration and purification to obtain the aromatic ring and heterocyclic ring derivatives.
Further, the molar ratio of the iron catalyst, the phenolic derivative, lithium methoxide and the bis (pinacolato) diborate was 0.02:0.2:1.2: 0.5.
Further, the molar ratio of the ligand, alkyl halide and phenolic derivative is 0.02:0.3: 0.2; the molar volume ratio of the ligand to the organic solvent is 0.02:1 mol/L.
Further, the phenolic derivative is 1-diethyl carbamate naphthalene, 1' -binaphthyl-4-diethyl carbamate, phenyl diethyl carbamate or 4-diethyl carbamate pyridine; the alkyl halide is bromocyclopentane, (bromomethyl) cyclohexane, bromocyclopentane, 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran, 3-bromobenzene propane or 1-benzyl-4-bromopiperidine.
Further, 1-diethyl carbamate naphthalene is prepared by the following method: adding sodium hydride into a dried tetrahydrofuran solution of 1-naphthol at the temperature of 0-1 ℃, heating to room temperature, stirring for 1-2 hours, then adding N, N-diethyl chloroformamide, stirring for 3-4 hours at the room temperature, dripping water at the temperature of 0-1 ℃ after complete reaction until no bubbles are generated, adding ethyl acetate, extracting for 2-4 times, 20-40 mL each time, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating in vacuum to constant weight, and recrystallizing residues with petroleum ether and ethyl acetate to obtain 1-diethyl carbamate naphthalene.
Further, the ligand is tetramethyl ethylenediamine or di-tert-valeryl methane, and the organic solvent is methyl tert-butyl ether or diethyl ether.
Further, in the step (3), ethyl acetate is used for extraction for 2-4 times, 10-20 mL of the extract is obtained each time, organic phases are combined and dried by anhydrous sodium sulfate, then vacuum concentration is carried out until the weight is constant, and finally, the mixture is purified by chromatographic column chromatography, wherein eluant is petroleum ether and ethyl acetate.
In summary, the invention has the following advantages:
1. the iron catalyst is applied to the reduction coupling reaction of the phenolic derivative and the alkyl halide for the first time, the iron catalyst is low in cost and non-toxic, the use of the phenolic derivative also reduces the preparation cost, the problems of high cost, high toxicity, environmental friendliness and the like of the catalyst and reaction raw materials are effectively solved, and the iron catalyst has a wide application prospect; the aromatic ring and heterocyclic ring derivatives are prepared by taking the phenol derivatives and alkyl halides as reactants, taking tetramethylethylenediamine as a ligand, taking lithium methoxide as an alkali and taking methyl tert-butyl ether as a solvent, and the preparation process is simple and easy to control, has low cost and no toxicity and is convenient to popularize and use.
2. The invention uses iron as a metal catalyst, has no toxicity, low cost and environmental protection, has unique advantages compared with metal catalysts such as palladium, nickel and the like, and enlarges the application prospect of the reduction coupling reaction. The reduction coupling reaction of the aryl diethylaminoformate and the brominated alkane is utilized to efficiently synthesize sp 2 -sp 3 Carbon-carbon bonds, avoiding the use of expensive and unstable metal nucleophiles (e.g., grignard reagents, boron reagents), save reaction costs. Among them, diethylaminoformyl group is used as a protecting group for phenol, which is inexpensive and more environmentally friendly unlike the commonly used sulfonyl protecting group, but reduction coupling reaction by diethylaminoaryl formate has hardly been studied heretofore due to its strong bond dissociation energy. In addition, the diethylamino formyl group is favored in organic synthesis, and is often used as a directing group to realize selective hydrocarbon activation on alpha position and beta position of aryl, so that the reaction has a very good application prospect.
3. Because the valence state of iron is variable and is not easy to control, the coupling reaction using iron as a catalyst is relatively less at present, and the reaction type is single. In addition, because the dissociation energy of the C-O bond is relatively strong, nitrogen, phosphine or carbene ligands with strong electron donors are generally needed for the carbon-oxygen bond activation reaction catalyzed by the transition metal, and the ligands are generally expensive, while the tetramethylethylenediamine ligand or the di-tert-valerylmethane used in the invention has low price and the dosage is catalytic amount, so the use cost of the reaction can be greatly reduced.
Drawings
FIG. 1 shows the product obtained in example 1 1 H NMR spectrum;
FIG. 2 shows the product obtained in example one 13 C NMR spectraA drawing;
FIG. 3 shows the product obtained in example two 1 H NMR spectrum;
FIG. 4 shows the product obtained in example two 13 C NMR spectrum;
FIG. 5 shows the product obtained in example III 1 H NMR spectrum;
FIG. 6 shows the product obtained in example III 13 C NMR spectrum;
FIG. 7 shows the product obtained in example four 1 H NMR spectrum;
FIG. 8 shows the product obtained in example four 13 C NMR spectrum;
FIG. 9 shows the product obtained in example V 1 H NMR spectrum;
FIG. 10 shows the product obtained in example V 13 C NMR spectrum.
Detailed Description
Example 1
A preparation method of 1-cyclopentyl naphthalene comprises the following steps:
(1) weighing ferrous iodide, 1-diethyl carbamate naphthalene, lithium methoxide and bis-pinacolato diborate under sealed and oxygen-free conditions to obtain a mixed raw material, connecting the double-row tube, and performing nitrogen pumping and air exchange for 3 times, and then replacing a rubber plug and performing nitrogen pumping and air exchange for 3 times at an interval of 4min each time; the molar ratio of ferrous iodide, 1-diethylaminoformate naphthalene, lithium methoxide and bis (pinacolato) diborate is 0.02:0.2:1.2: 0.5;
(2) adding tetramethylethylenediamine, bromocyclopentane and methyl tert-butyl ether into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting at a constant temperature of 70 ℃ for 16 h; the molar ratio of tetramethyl ethylenediamine, bromocyclopentane and 1-diethyl carbamate naphthalene is 0.02:0.3: 0.2; the molar volume ratio of the tetramethylethylenediamine to the methyl tert-butyl ether is 0.02:1 mol/L;
(3) quenching the reaction in the step (2) by using saturated solution of ammonium chloride, extracting for 3 times by using ethyl acetate, wherein each time is 10mL, combining organic phases, drying by using anhydrous sodium sulfate, concentrating in vacuum to constant weight, and finally purifying by using chromatographic column chromatography, wherein an eluent is petroleum ether to obtain the 1-cyclopentyl naphthalene.
Wherein, the 1-diethyl carbamate naphthalene is prepared by the following method: adding sodium hydride into a dried tetrahydrofuran solution of 1-naphthol at the temperature of 0 ℃, heating to room temperature and stirring for 1h, then adding N, N-diethyl chloroformamide, stirring for 3h at the room temperature, dripping water at the temperature of 0 ℃ after complete reaction until no bubbles are generated, adding ethyl acetate, extracting for 3 times (30 mL each time), combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating in vacuum to constant weight, and recrystallizing residues by using petroleum ether and ethyl acetate to obtain the 1-diethyl carbamate naphthalene.
The reaction process of this example is as follows:
Figure BDA0002409097130000061
33mg of 1-cyclopentylnaphthalene was obtained in 84% yield by the above-mentioned method. Subjecting the resulting product to a nuclear magnetic resonance test, which 1 H、 13 The C nuclear magnetic resonance spectrogram is shown in figures 1-2. As shown in FIGS. 1-2, the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.3Hz,1H),7.85(d,J＝7.8Hz,1H),7.75–7.66(m,1H),7.50(q,J＝8.7,7.7Hz,2H),7.43(d,J＝4.9Hz,2H),3.79(p,J＝7.8,7.4Hz,1H),2.21(p,J＝7.6,6.3Hz,2H),1.95–1.72(m,6H). 13 C NMR(101MHz,Chloroform-d)δ142.15,133.86,132.22,128.75,126.25,125.56,125.51,125.25,123.95,121.96,41.19,33.58,25.33。
example 2
A method for preparing 1- (cyclohexylmethyl) naphthalene comprises the following steps:
(1) weighing ferrous iodide, 1-diethyl carbamate naphthalene, lithium methoxide and bis-pinacolato diborate under sealed and oxygen-free conditions to obtain a mixed raw material, connecting the double-row tube, and performing nitrogen pumping and air exchange for 3 times, and then replacing a rubber plug and performing nitrogen pumping and air exchange for 3 times at an interval of 4min each time; the molar ratio of ferrous iodide, 1-diethylaminoformate naphthalene, lithium methoxide and bis (pinacolato) diborate is 0.02:0.2:1.2: 0.5;
(2) adding tetramethylethylenediamine, (bromomethyl) cyclohexane and methyl tert-butyl ether into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting for 16h at a constant temperature of 70 ℃; the molar ratio of tetramethylethylenediamine, (bromomethyl) cyclohexane and 1-diethylaminoformate naphthalene is 0.02:0.3: 0.2; the molar volume ratio of the tetramethylethylenediamine to the methyl tert-butyl ether is 0.02:1 mol/L;
(3) quenching the reaction in the step (2) by using saturated ammonium chloride solution, extracting for 3 times by using ethyl acetate, wherein the concentration is 10mL each time, combining organic phases, drying by using anhydrous sodium sulfate, concentrating under vacuum to constant weight, and finally purifying by using chromatographic column chromatography, wherein an eluent is petroleum ether to obtain the 1- (cyclohexylmethyl) naphthalene.
Wherein, the 1-diethyl carbamate naphthalene is prepared by the following method: adding sodium hydride into a dried tetrahydrofuran solution of 1-naphthol at the temperature of 0 ℃, heating to room temperature and stirring for 1h, then adding N, N-diethyl chloroformamide, stirring for 3h at the room temperature, dripping water at the temperature of 0 ℃ after complete reaction until no bubbles are generated, adding ethyl acetate, extracting for 3 times (30 mL each time), combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating in vacuum to constant weight, and recrystallizing residues by using petroleum ether and ethyl acetate to obtain the 1-diethyl carbamate naphthalene.
The reaction process of this example is as follows:
Figure BDA0002409097130000071
33.2mg of 1- (cyclohexylmethyl) naphthalene was obtained in 74% yield by the above-mentioned method. Subjecting the resulting product to a nuclear magnetic resonance test, which 1 H、 13 The C nuclear magnetic resonance spectrogram is shown in figures 3-4. As shown in FIGS. 3 to 4, the test results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.02(d,J＝8.3Hz,1H),7.84(d,J＝7.9Hz,1H),7.69(d,J＝8.1Hz,1H),7.52–7.46(m,1H),7.48–7.42(m,1H),7.37(t,J＝7.6Hz,1H),7.26(d,1H),2.92(d,J＝6.7Hz,2H),1.75–1.65(m,5H),1.63(d,J＝9.6Hz,1H),1.18–1.12(m,3H),1.06(dd,J＝13.5,10.1Hz,2H). 13 CNMR(151MHz,acetone)δ132.20,128.73,127.06,123.50,121.91,121.22,120.30,120.07,120.04,119.05,36.03,33.74,28.53,21.40,21.14。
example 3
A method for preparing 1- (cyclohexylmethyl) naphthalene comprises the following steps:
(1) weighing ferrous iodide, 1' -binaphthyl-4-diethylamino formate, lithium methoxide and bis-pinacol diboron ester under sealed and oxygen-free conditions to obtain a mixed raw material, connecting the double-row pipes, performing nitrogen gas pumping for 3 times, replacing the rubber plug, and performing nitrogen gas pumping for 3 times at intervals of 4min each time; the molar ratio of ferrous iodide, 1' -binaphthyl-4-diethylamino formate, lithium methoxide and bis (pinacolato) diborate is 0.02:0.2:1.2: 0.5;
(2) adding tetramethylethylenediamine, bromocyclopentane and methyl tert-butyl ether into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting at a constant temperature of 70 ℃ for 16 h; the molar ratio of tetramethylethylenediamine, bromocyclopentane and 1,1' -binaphthyl-4-diethylamino formate is 0.02:0.3: 0.2; the molar volume ratio of the tetramethylethylenediamine to the methyl tert-butyl ether is 0.02:1 mol/L;
(3) quenching the reaction in the step (2) by using saturated solution of ammonium chloride, extracting for 3 times by using ethyl acetate, wherein each time is 30mL, combining organic phases, drying by using anhydrous sodium sulfate, concentrating under vacuum to constant weight, and finally purifying by using chromatographic column chromatography, wherein an eluent is petroleum ether to obtain the 1- (cyclohexylmethyl) naphthalene.
The reaction process of this example is as follows:
Figure BDA0002409097130000081
41.9mg of 1- (cyclohexylmethyl) naphthalene was obtained in 65% yield by the above-mentioned method. Subjecting the resulting product to a nuclear magnetic resonance test, which 1 H、 13 The C nuclear magnetic resonance spectrogram is shown in figures 5-6. As shown in FIGS. 5 to 6, the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.6Hz,1H),7.96(d,J＝8.1Hz,2H),7.65–7.55(m,2H),7.54–7.43(m,6H),7.34–7.26(m,2H),3.92(p,J＝7.7Hz,1H),2.32(dhept,J＝10.9,3.7Hz,2H),2.01–1.77(m,6H). 13 C NMR(101MHz,cdcl3)δ141.98,138.90,136.44,133.52,133.20,133.05,132.25,128.11,127.95,127.74,127.60,127.39,126.75,125.90,125.77,125.42,125.33,124.12,121.58,41.34,33.82,33.62,25.43。
example 4
A process for the preparation of 4- (6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) pyridine comprising the steps of:
(1) weighing ferrous iodide, 4-diethylamino formate pyridine, lithium methoxide and bis-pinacolato diborate under sealed and oxygen-free conditions to obtain a mixed raw material, connecting the double-row tube, and performing nitrogen pumping and air exchange for 3 times, and then replacing a rubber plug and performing nitrogen pumping and air exchange for 3 times at an interval of 4min each time; the molar ratio of ferrous iodide, 4-diethylamino formate pyridine, lithium methoxide and bis (pinacolato) diborate is 0.02:0.2:1.2: 0.5;
(2) adding di-tert-valeryl methane, 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran and methyl tert-butyl ether into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting for 16H at a constant temperature of 90 ℃; the molar ratio of di-tert-valerylmethane, 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran, and 4-diethylaminoformate pyridine is 0.02:0.3: 0.2; the molar volume ratio of the di-tert-valeryl methane to the methyl tert-butyl ether is 0.02:1 mol/L;
(3) quenching the reaction in the step (2) by using saturated solution of ammonium chloride, extracting for 3 times by using ethyl acetate, wherein each time is 10mL, combining organic phases, drying by using anhydrous sodium sulfate, concentrating in vacuum to constant weight, and finally purifying by using chromatographic column chromatography, wherein an eluent is petroleum ether to obtain the 4- (6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) pyridine.
The reaction process of this example is as follows:
Figure BDA0002409097130000101
31.6mg of 4- (6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) pyridine was prepared in the above manner with a yield of 65%. Subjecting the resulting product to a nuclear magnetic resonance test, which 1 H、 13 The C nuclear magnetic resonance spectrogram is shown in figures 7-8. As shown in FIGS. 7 to 8, the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J＝5.0Hz,2H),7.09(d,J＝5.0Hz,2H),4.55(t,J＝3.6Hz,1H),3.85(ddd,J＝11.0,7.3,3.3Hz,1H),3.71(dt,J＝9.7,6.8Hz,1H),3.48(dt,J＝10.7,4.9Hz,1H),3.36(dt,J＝9.7,6.5Hz,1H),2.59(t,J＝7.7Hz,2H),1.91–1.76(m,2H),1.75–1.45(m,8H),1.37(dt,J＝9.0,5.2Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ149.58,123.89,98.90,67.50,62.41,35.15,30.76,30.19,29.59,28.97,26.02,25.46,19.71。
example 5
A method for preparing 1-benzyl-4- (naphthalen-1-yl) piperidine comprising the steps of:
(1) weighing ferrous iodide, 1-diethyl carbamate naphthalene, lithium methoxide and bis-pinacolato diborate under sealed and oxygen-free conditions to obtain a mixed raw material, connecting the double-row tube, and performing nitrogen pumping and air exchange for 3 times, and then replacing a rubber plug and performing nitrogen pumping and air exchange for 3 times at an interval of 4min each time; the molar ratio of ferrous iodide, 1-diethylaminoformate naphthalene, lithium methoxide and bis (pinacolato) diborate is 0.02:0.2:1.2: 0.5;
(2) adding tetramethylethylenediamine, 1-benzyl-4-bromopiperidine and methyl tert-butyl ether into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting at a constant temperature of 70 ℃ for 16 h; the molar ratio of tetramethyl ethylenediamine, 1-benzyl-4-bromopiperidine and 1-diethyl carbamate naphthalene is 0.02:0.3: 0.2; the molar volume ratio of the tetramethylethylenediamine to the methyl tert-butyl ether is 0.02:1 mol/L;
(3) quenching the reaction in the step (2) by using saturated solution of ammonium chloride, extracting for 3 times by using ethyl acetate, wherein each time is 10mL, combining organic phases, drying by using anhydrous sodium sulfate, concentrating in vacuum to constant weight, and finally purifying by using chromatographic column chromatography, wherein an eluent is petroleum ether to obtain the 1-benzyl-4- (naphthalene-1-yl) piperidine.
The reaction process of this example is as follows:
Figure BDA0002409097130000111
32.5mg of 1- (cyclohexylmethyl) naphthalene was obtained in 54% yield by the above-mentioned method. The resulting product was subjected to a nuclear magnetic resonance test,it is composed of 1 H、 13 The C nuclear magnetic resonance spectrogram is shown in figures 9-10. As shown in FIGS. 9 to 10, the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J＝8.3Hz,1H),7.89–7.83(m,1H),7.71(dd,J＝6.9,2.5Hz,1H),7.51(td,J＝6.7,6.0,2.7Hz,1H),7.51–7.41(m,3H),7.46–7.35(m,3H),7.35(d,J＝7.5Hz,1H),7.29(dd,J＝10.0,4.3Hz,1H),3.63(s,2H),3.34(tt,J＝10.3,5.5Hz,1H),3.11(dd,J＝11.5,3.2Hz,2H),2.27(td,J＝11.0,4.2Hz,2H),2.04–1.91(m,4H). 13 C NMR(101MHz,Chloroform-d)δ142.12,138.29,133.90,131.33,129.35,129.01,128.22,127.04,126.52,125.71,125.29,122.97,122.49,63.54,54.54,37.56,33.09。
comparative example
Figure BDA0002409097130000112
Daniel j.weix in 2012 reported that the nickel-catalyzed reductive coupling reaction of aryl halide and alkyl halide using zinc as a reducing agent also can obtain a relatively good yield, but the nickel catalyst applied in the method has a high biotoxicity compared with an iron catalyst, is relatively unsuitable for the later modification of drugs, and the halobenzene used in the method is relatively expensive compared with a phenol derivative and is not friendly to the environment.
While the present invention has been described in detail with reference to the illustrated embodiments, it should not be construed as limited to the scope of the present patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.

Claims (6)

1. The application of iron catalyst in the reduction coupling reaction of phenol derivatives and alkyl halides to prepare aromatic ring and heterocyclic derivatives is characterized in that the iron catalyst is ferrous iodide, and the phenol derivatives are 1-diethyl carbamate naphthalene, 1' -binaphthyl-4-diethyl carbamate, diethyl carbamate phenyl ester or 4-diethyl carbamate pyridine; the alkyl halide is bromocyclopentane, (bromomethyl) cyclohexane, bromocyclopentane, 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran, 3-bromobenzene propane or 1-benzyl-4-bromopiperidine; the ligand is tetramethyl ethylenediamine or di-tert-valeryl methane, and the organic solvent is methyl tert-butyl ether or diethyl ether; and adding lithium methoxide and bis (pinacolato) diborate; the aromatic ring and heterocyclic ring derivatives are 1-cyclopentyl naphthalene, 1- (cyclohexylmethyl) naphthalene, 4- (6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) pyridine or 1-benzyl-4- (naphthalene-1-yl) piperidine.
2. A preparation method of aromatic ring and heterocyclic derivatives is characterized in that the iron catalyst of claim 1 is adopted to catalyze the reduction coupling reaction of phenolic derivatives and alkyl halides to prepare the aromatic ring and heterocyclic derivatives;
wherein the iron catalyst is ferrous iodide, and the phenolic derivative is 1-diethyl carbamate naphthalene, 1' -binaphthyl-4-diethyl carbamate, phenyl diethyl carbamate or 4-diethyl carbamate pyridine; the alkyl halide is bromocyclopentane, (bromomethyl) cyclohexane, bromocyclopentane, 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran, 3-bromobenzene propane or 1-benzyl-4-bromopiperidine; the ligand is tetramethyl ethylenediamine or di-tert-valeryl methane, and the organic solvent is methyl tert-butyl ether or diethyl ether; and adding lithium methoxide and bis (pinacolato) diborate; the aromatic ring and heterocyclic ring derivatives are 1-cyclopentyl naphthalene, 1- (cyclohexylmethyl) naphthalene, 4- (6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) pyridine or 1-benzyl-4- (naphthalene-1-yl) piperidine.
3. The process for the preparation of aromatic and heterocyclic derivatives according to claim 2, characterized by comprising the following steps:
(1) weighing an iron catalyst, a phenol derivative, lithium methoxide and bis-pinacolato diborate under a sealed and oxygen-free condition to obtain a mixed raw material, connecting the two rows of tubes, and performing nitrogen gas pumping and exchanging for 2-4 times, replacing a rubber plug, and then performing nitrogen gas pumping and exchanging for 2-4 times at an interval of 3-5 min each time; the molar ratio of the iron catalyst, the phenolic derivative, the lithium methoxide and the bis (pinacolato) diborate is 0.01-0.03: 0.1-0.3: 1-1.5: 0.4-0.6;
(2) adding a ligand, an alkyl halide and an organic solvent into the mixed raw material obtained in the step (1) in a nitrogen atmosphere, and reacting at a constant temperature of 50-90 ℃ for 12-16 h; the molar ratio of the ligand to the alkyl halide to the phenol derivative is 0.01-0.03: 0.2-0.4: 0.1-0.3; the molar volume ratio of the ligand to the organic solvent is 0.01-0.03: 1 mol/L;
(3) and (3) quenching the reaction in the step (2) by using an ammonium chloride saturated solution, and then sequentially carrying out extraction, drying, vacuum concentration and purification to obtain the aromatic ring and heterocyclic ring derivatives.
4. The process for the preparation of aromatic and heterocyclic derivatives according to claim 2, characterized in that the molar ratio of iron catalyst, phenolic derivative, lithium methoxide and bis-pinacolato diborate is 0.02:0.2:1.2: 0.5.
5. The process for the preparation of aromatic and heterocyclic derivatives as claimed in claim 2, characterized in that the molar ratio of the ligand, the alkyl halide and the phenolic derivative is 0.02:0.3: 0.2; the molar volume ratio of the ligand to the organic solvent is 0.02:1 mol/L.
6. The method for preparing aromatic ring and heterocyclic derivative according to claim 2, wherein in step (3), ethyl acetate is used for extraction for 2-4 times, 10-20 mL each time, the organic phases are combined and dried by anhydrous sodium sulfate, then vacuum concentration is carried out until the weight is constant, and finally the mixture is purified by chromatographic column chromatography, and the eluent is petroleum ether and ethyl acetate.
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