阅读说明：本技术 一种硫粉促进的无机铵为氮源的芳香醛转化为芳香腈的方法 (Method for converting aromatic aldehyde into aromatic nitrile by using inorganic ammonium as nitrogen source and promoted by sulfur powder ) 是由 龚行 周方元 尹嘉雯 于 2020-06-24 设计创作，主要内容包括：本发明公开了一种芳香醛转化为芳香腈的方法。该方法是硫粉促进的无机铵为氮源的芳香醛一锅反应高收率的转化为芳香腈。该方法具有不需要金属参与,不需要使用强氧化物,且反应对空气兼容、易于扩增至克级规模等优点,克服了现有技术中反应条件苛刻,如需要使用昂贵的金属试剂,或需使用有毒试剂,操作复杂,官能团相容性低等问题。(The invention discloses a method for converting aromatic aldehyde into aromatic nitrile. The method is used for converting aromatic aldehyde promoted by sulfur powder and using inorganic ammonium as a nitrogen source into aromatic nitrile in a one-pot reaction with high yield. The method has the advantages of no need of metal participation, no need of using strong oxide, compatible reaction to air, easy amplification to gram-scale and the like, and solves the problems of harsh reaction conditions, complex operation, low functional group compatibility and the like in the prior art, such as the need of using expensive metal reagents or toxic reagents.)

1. A method for converting aromatic aldehyde into aromatic nitrile by using inorganic ammonium as a nitrogen source and promoted by sulfur powder. The method comprises the following steps: performing one-pot reaction on substituted aromatic aldehyde in the formula 1 at 120 ℃ under the air condition to obtain aromatic nitrile in the formula 2;

R-C≡N

formula 2

Wherein the content of the first and second substances,

r is selected from benzene and its derivatives, naphthalene and its derivatives, anthracene, pyridine, quinoline, indole, thiophene or benzoaromatic heterocycle.

2. The method of claim 1, wherein the method comprises the steps of: the substituted aromatic aldehyde of formula 1 is 4-methylbenzaldehyde, 4-butylbenzaldehyde, 3, 5-dimethylbenzaldehyde, 4-methoxybenzaldehyde, 3-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, 2, 4-dimethoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 4-benzyloxybenzaldehyde, 4-methylthiobenzaldehyde, 4-hydroxybenzaldehyde, 4-aminobenzaldehyde, 4-N, N-dimethylaminobenzaldehyde, 4-N-acetamidobenzaldehyde, 4-phenylbenzaldehyde, 4- (4-methyl-1-piperazinyl) benzaldehyde, 4-cyanobenzaldehyde, naphthaldehyde, 2-naphthaldehyde, methyl-1-piperazinyl-benzaldehyde, 4-cyanobenzaldehyde, naphthaldehyde, 2-naphthaldehyde, or mixtures thereof, 6-methoxy-2-naphthaldehyde, 9-anthracene formaldehyde, 3-pyridine formaldehyde, 4-isoquinoline formaldehyde, 6-quinoline benzaldehyde, benzothiophene-3-formaldehyde and benzofuran-5-formaldehyde.

3. The method of claim 1, wherein the method comprises the steps of: the reaction temperature is 80-120 ℃, and the reaction time is 8-12 hours.

4. The method of claim 1, wherein the method comprises the steps of: the nitrogen source for the reaction is ammonium sulfate, and the dosage of the ammonium sulfate is 0.5-0.25 millimole.

5. The method of claim 1, wherein the method comprises the steps of: the alkali used in the reaction is sodium carbonate, and the dosage of the sodium carbonate is 0.5-1.0 millimole.

6. The method of claim 1, wherein the method comprises the steps of: the additive for the reaction is sulfur powder, and the dosage of the additive is 0.5-1.0 millimole.

7. The method of claim 1, wherein the method comprises the steps of: the solvent for the reaction was dimethyl sulfoxide, the volume of which was 0.5 ml.

8. The method for converting aromatic aldehyde into aromatic nitrile by using inorganic ammonium as a nitrogen source promoted by sulfur powder as claimed in any one of claims 1 to 7, wherein the method comprises the following steps: the aromatic aldehyde of formula 1 is reacted at 120 ℃ for 10 hours to obtain the aromatic nitrile of formula 2.

9. The method of claim 8, wherein the aromatic aldehyde is converted to an aromatic nitrile by using inorganic ammonium as a nitrogen source, wherein the inorganic ammonium is promoted by sulfur powder, and the method comprises the following steps: the concentration of the aromatic formaldehyde in the dimethyl sulfoxide is 1.0 mol/L.

Technical Field

The invention relates to a synthetic method of aromatic nitrile, in particular to a method for converting aromatic aldehyde into aromatic nitrile promoted by sulfur powder under the condition of no metal, belonging to the field of synthesis of medical intermediates and fine organic synthesis.

Background

Nitrile compounds are widely found in pharmaceuticals, natural products, agrochemicals and functional materials (as shown below). Escitalopram (W)₁) Can be used for treating depression and anxiety [ Sanchez S., Basic ]&Clin.Pharmacol.Toxicol.,2006,99(2):91-95](ii) a Letrozole (W)₂) Has effects in inhibiting tumor growth and can be used for treating breast cancer [ Motiwala H.F., Yin Q., AubeJ., Molecules,2016,21(1):45](ii) a Rilpivirine (W)₃) Is a medicine for treating HIV (GurjarJ., Bater J., Fokin V.V., chem.Eur.J.,2019,25(8):1906-](ii) a Nilvadipine (W)₄) Is often used for treating hypertension and angina [ Ogasawara K., Noda A., Ogawa A., et al.Nucl Med.Commun.,2003,24(1):71-76](ii) a Febuxostat (W)₅) Gout can be treated by reducing urea [ Chen H., Sun S.J., Zhou Y.H., et al tetrahedron Lett.,2019,60(21):1434-](ii) a Kribolol (W)₆) Can be used for treating eczema [ Eichenfield L.F., Call R.S., Tschen E.et al.J.Am.Acad.Dermatol.2017, 77(4): 641-649-](ii) a Vildagliptin (W)₇) Is an oral antidiabetic drug (Ghosh P., Subba R., Tetrahedron Lett.,2013,54(36):4885-](ii) a Zaleplon (W)₈) Has sedative effect and is a hypnotic [ Mitra B, Pariyar G.C., Ghosh P., et al. tetrahedron Lett.,2017,58(23):2298-]。

However, the existing methods for synthesizing aromatic nitriles often require the use of highly toxic metal cyanides [ Wu Q., LuoY., YouJ.S., et al.J.Am.Chem.Soc.,2016,138(9): 2885-once 2888], metal catalysts [ (a) Shigekazu Y., Yasuyuki Y., Chem.Lett.,1990,19(4):571-574.(b) Movasssagha B., Shokrri S., Tetrahedron Lett.,2005,46(40): 6923-once 6925 (c) Red M.B.M., Pasha M.A., Chinese.Lett., 2010,21 (1025-once) 1028-once (c) Laulh e S., Cheri S., Nan S., Synntz H.H., Aust H.J.S., Aust H.W.S., Aust H.J.S., Aust.J.S., W.J.20, W.J.J.S., Aust H.20, W.J.J.20, W.J.J.H.20, J.S., S., W.20, J.20, J.J.J.H.J.J.H.D.H.H.S., S., W.35, W.D., S., W.D., S., W.D., S., W., W.D.D., W.D. H., W. 20, W.D., S., ran r.a., namjoshi v., synthetic.commun.,2010,40(4):494 @497 ], or the use of toxic sodium azide (Schmidt reaction) [ Mitra b., Pariyar g g.c., Ghosh p., et al.tetrahedron lett.,2017,58(23): 2298-.

Disclosure of Invention

In order to achieve the technical purpose, the invention provides a method for converting aromatic aldehyde into aromatic nitrile in high yield by using inorganic ammonium as a nitrogen source promoted by sulfur powder under the condition of no metal participation, which comprises the following steps: carrying out one-pot reaction on the substituted aromatic aldehyde of the formula 1 at 120 ℃ under the air condition to obtain aromatic nitrile of the formula 2;

wherein the content of the first and second substances,

r is selected from benzene and its derivatives, naphthalene and its derivatives, anthracene, pyridine, quinoline, indole, thiophene or benzoaromatic heterocycle;

in a preferred embodiment, the aldehyde of formula 1 is 4-methylbenzaldehyde, 4-butylbenzaldehyde, 3, 5-dimethylbenzaldehyde, 4-methoxybenzaldehyde, 3-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, 2, 4-dimethoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 4-benzyloxybenzaldehyde, 4-methylthiobenzaldehyde, 4-hydroxybenzaldehyde, 4-aminobenzaldehyde, 4-N, N-dimethylaminobenzaldehyde, 4-acetamidobenzaldehyde, 4-phenylbenzaldehyde, 4- (4-methyl-1-piperazinyl) benzaldehyde, 4-cyanobenzaldehyde, naphthaldehyde, 2-naphthaldehyde, methyl-1-piperazinyl-benzaldehyde, 4-cyanobenzaldehyde, 4-nitrobenzaldehyde, 2-naphthaldehyde, 3, 6-methoxy-2-naphthaldehyde, 9-anthracene formaldehyde, 3-pyridine formaldehyde, 4-isoquinoline formaldehyde, 6-quinoline benzaldehyde, benzothiophene-3-formaldehyde and benzofuran-5-formaldehyde.

In a preferred embodiment, the nitrile of the formula 2 is 4-methylbenzonitrile, 4-butylbenzonitrile, 3, 5-dimethylbenzonitrile, 4-methoxybenzonitrile, 3-methoxybenzonitrile, 2-methoxybenzonitrile, 3, 5-dimethoxybenzonitrile, 3, 4-dimethoxybenzonitrile, 2, 4-dimethoxybenzonitrile, 3,4, 5-trimethoxybenzonitrile, 4-benzyloxybenzonitrile, 4-methylthiobenzonitrile, 4-hydroxybenzonitrile, 4-aminobenzonitrile, 4-N, N-dimethylaminobenzonitrile, 4-N-acetamidobenzonitrile, 4-phenylbenzonitrile, 4- (4-methyl-1-piperazinyl) benzonitrile, 4-cyanobenzonitrile, naphthanenitrile, 2-naphthanenitrile, 6-methoxy-2-naphthonitrile, 9-anthracenecarbonitrile, 3-pyridinecarbonitrile, 4-isoquinolinecarbonitrile, 6-quinolinecarbonitrile, benzothiophene-3-carbonitrile, benzofuran-5-carbonitrile.

In a preferred scheme, the nitrogen source is at least one of ammonium iodide, ammonium chloride, ammonium acetate, ammonium formate, ammonium hexafluorophosphate and ammonium sulfate; ammonium hexafluorophosphate, ammonium acetate or ammonium sulfate is more preferable; most preferred is ammonium sulfate.

In a preferred scheme, the base is at least one of potassium carbonate, potassium tert-butoxide, potassium phosphate, sodium carbonate, potassium acetate or sodium bicarbonate; more preferably potassium carbonate, sodium carbonate or potassium phosphate; the most preferred base is sodium carbonate.

In a preferred scheme, the additive is at least one of sulfur powder and elementary iodine; the most preferred additive is sulfur powder.

In the preferred scheme, ammonium sulfate is a nitrogen source, the dosage of the ammonium sulfate is 0.5-1.0 equivalent, the time is 8-12 hours, and the reaction temperature is 80-120 ℃. In a further preferred scheme, the using amount of the sulfur powder is 0.5-2.0 equivalent, the time is 8-12 hours, and the reaction temperature is 80-120 ℃. The dosage of the nitrogen source and the additive is too low, and the yield is reduced. Too short a reaction time reduces the yield, while too long a reaction time reduces the yield. The best reaction effect can be achieved within the preferable reaction time and temperature range.

In a preferred scheme, the solvent adopted in the reaction is at least one of toluene, N-dimethylformamide, tetrahydrofuran, methanol, water, 1, 4-dioxane, pyridine, acetone and ethyl acetate, and the solvent is more preferably 1, 4-dioxane, pyridine and dimethyl sulfoxide; most preferred is dimethyl sulfoxide.

The reaction equation in the synthesis of the aromatic nitrile of the present invention is as follows.

According to the technical scheme, the aromatic aldehyde, the nitrogen source, the alkali, the additive and the solvent are added into dimethyl sulfoxide, the mixture is placed into a hot bath kettle with a set temperature under a closed condition, and magnetic stirring is carried out. After the reaction for the set time, the reaction mixture was cooled to room temperature. Then extracted with ethyl acetate and the organic phases are combined. Washing the organic phase with saturated saline solution, separating the liquid, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by thin layer chromatography with petroleum ether/ethyl acetate as developing agent to obtain pure product.

The method for synthesizing the aromatic nitrile comprises the following steps:

0.5mmol of 4-methylbenzaldehyde, 0.5mmol of ammonium sulfate, 0.5mmol of sodium carbonate, 1.0mmol of sulfur powder, and 0.5ml of dimethyl sulfoxide were weighed and charged into a reaction tube. And (3) putting the reaction tube into a hot bath kettle with a set temperature under an air atmosphere, and magnetically stirring to react for 10 hours. The reaction was cooled to room temperature. Then extracted with ethyl acetate and the organic phases are combined. Washing the organic phase with saturated saline solution, separating the liquid, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was purified as petroleum ether: separating the crude product by thin layer chromatography with ethyl acetate (200: 1) as developing agent to obtain pure product.

Compared with the prior art, the technical scheme of the invention has the following advantages and effects:

1) the technical scheme of the invention provides a method for converting aromatic aldehyde, which is promoted by sulfur powder and takes inorganic ammonium as a nitrogen source, into aromatic nitrile in a one-pot high yield manner.

2) The technical scheme of the invention avoids using toxic reagents and strong oxides with potential explosion risks.

3) The technical scheme of the invention has the advantages of compatibility to air, low cost, simple operation, convenient reaction scale expansion to gram level and the like; overcomes the defects of high reagent toxicity, high cost, complex operation, low functional group compatibility and the like in the prior art.

Drawings

FIG. 1 shows the product obtained in example 4¹H NMR chart;

FIG. 2 shows the product obtained in example 4¹³C NMR chart;

FIG. 3 shows the product obtained in example 5¹H NMR chart;

FIG. 4 shows the product obtained in example 5¹³C NMR chart.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, reagents, test methods and the like for carrying out the present invention are general and common general knowledge in the art except for those specifically mentioned below, and the present invention is not particularly limited.