Method for synthesizing beta-nitro alcohol by one-pot method using alcohol compound as starting material

Abstract

The application relates to a one-pot synthesis method of beta-nitro alcohol by taking an alcohol compound as a starting raw material, which is characterized by the following steps: taking an alcohol and a nitro compound as raw materials, reacting under the action of sulfuric fluoride gas and an alkaline catalyst at room temperature, and separating and purifying to obtain a beta-nitro alcohol compound; the beta-nitro alcohol compound has the following structural formula: wherein R1 and R2 are phenyl, substituted phenyl, heterocyclic aryl, fused ring aryl, substituted fused ring aryl, alkyl or hydrogen atom; R3 and R4 are aryl, hydrogen atom or alkyl. The conversion method of the beta-nitro alcohol by the alkali promotion of the alcohol directly realizes the construction of a C(sp3)-C(sp3) bond, the reaction condition is mild, the operation is simple, the requirement of instrument equipment is low, the alcohol is used as the reaction raw material, the price is low, the source is wide, the yield of the prepared beta-nitro alcohol compound is high, the substrate application range is wide, most functional groups can be tolerated, and a new path is provided for the synthesis of complex beta-nitro alcohol.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a method for synthesizing beta-nitro alcohol by one-pot method using alcohol compounds as starting materials. BACKGROUND

[0002] Beta-nitro alcohol is an important nitro compound, and is also a key chiral building block for the synthesis of various pharmaceutical intermediates, bioactive substances and fine chemicals. For example, beta-nitro alcohol can be used to synthesize various drugs, such as some anticancer drugs, antibiotics, cardiovascular drugs, etc.; at the same time, it can be used as an intermediate for the synthesis of juvenile hormone, and can be used to prevent harvest loss and pest reproduction; as an intermediate for the synthesis of diuretics, it can be used to treat heart, kidney and other diseases; as an intermediate for the synthesis of antimalarial drugs, it can be used to treat malaria, etc. In the field of chemical transformation, the double functional groups of beta-nitro alcohol can be easily converted into other functional groups (Formula 1) through various reactions. For nitro group, it can be easily reduced to amino group under mild conditions (path a); in addition, Nef reaction of nitroalkane provides another way for the preparation of carbonic acid compounds (path b); under free radical conditions, the nitro group can be replaced by hydrogen atom (path c); as for the hydroxyl group, the dehydration process can be used to prepare nitroalkene (path d), which is one of the most commonly used Michael acceptors.

[0003]

[0004] At present, the reaction for synthesizing beta-nitro alcohol is mainly Henry condensation reaction of nitroalkane and aldehyde ketone under the catalysis of alkali. Its main advantage lies in that it can generate compounds with multiple functional groups in one step, and the reaction conditions are relatively mild and the yield is relatively high. However, the aldehyde ketone used in Henry reaction has certain toxicity, and the steric hindrance of the reaction substrate has a great influence on the reaction activity. The reaction of ketone with large steric hindrance is very slow, and side reactions often occur. Therefore, it is necessary to develop a new type of green and safe method for synthesizing beta-nitro alcohol compounds SUMMARY

[0005] In view of the deficiencies in the prior art, and also in order to provide a new synthesis route, the present application aims to develop a synthesis method with mild conditions and simple route for converting alcohol compounds into beta-nitro alcohol molecules by one-pot method based on alcohol compounds with low price, and the synthesized beta-nitro alcohol substrates are of various types and have wide application range.

[0006] To achieve the above-mentioned purpose, the present application provides the following technical scheme:

[0007] The application discloses a method for synthesizing a beta-nitro alcohol by one-pot method with an alcohol compound as a starting material, which comprises the following steps: taking an alcohol and a nitro compound as raw materials, reacting at room temperature under the action of sulfuryl fluoride gas and an alkaline catalyst, and then separating and purifying to obtain a beta-nitro alcohol compound; the beta-nitro alcohol compound has the following structural formula wherein, R1 and R2 are phenyl, substituted phenyl, heterocyclic aryl, condensed ring aryl, substituted condensed ring aryl, alkyl or hydrogen atom; R3 and R4 are aryl, hydrogen atom or alkyl.

[0008] Further, the alcohol has the following structural formula: wherein, R1 and R2 are phenyl, substituted phenyl, heterocyclic aryl, condensed ring aryl, substituted condensed ring aryl, alkyl or hydrogen atom; the nitro compound has the following structural formula: wherein, R3 and R4 are aryl, hydrogen atom or alkyl.

[0009] Further, the solvent is acetonitrile, dimethyl sulfoxide, dichloromethane, methanol, acetonitrile, tetrahydrofuran or ethanol, and is preferably dimethyl sulfoxide.

[0010] Further, the alkaline catalyst is potassium carbonate, sodium hydroxide, DABCO, DMAP, sodium hydroxide or sodium methoxide, and is preferably potassium carbonate.

[0011] Further, the molar ratio of the alcohol to the nitro compound is 1:1-10.

[0012] Further, the step of separating and purifying comprises the following steps: after the reaction is completed, the reaction liquid is extracted with water and dichloromethane, the obtained dichloromethane layer is dried with anhydrous sodium sulfate, filtered, and rotary dried, and then the residue is purified by silica gel column chromatography.

[0013] The alcohol compound is widely present in chemical raw materials, is low in price, green and safe, and has various types. Direct conversion of the alcohol compound into a beta-nitro alcohol compound provides a green synthesis path for construction of a carbon-carbon bond. At present, the method for synthesizing the beta-nitro alcohol compound from the alcohol compound as a starting material by one-pot method is still less. In the application, the beta-nitro alcohol compound is synthesized by one-pot method from the alcohol compound, the synthesis general formula is as shown in formula 2, the oxidation-condensation reaction is connected in series, first, the alcohol compound is oxidized into a corresponding aldehyde ketone compound under the action of an alkali, DMSO and sulfuryl fluoride, and then the Henry condensation reaction is generated between the aldehyde ketone compound and the nitro compound under the action of the alkali to obtain the final product, the beta-nitro alcohol compound. The application has the advantages of mild conditions, simple operation and high yield, and provides a new effective route for preparation of the beta-nitro alcohol.

[0014]

[0015] The beneficial effects of the present application are: in the currently reported studies, the beta-nitro alcohol is obtained by reacting aldehyde ketone compounds with nitro compounds. The present application provides a new route for synthesizing beta-nitro alcohol, which realizes the construction of C(sp3)-C(sp3) bond directly by using alcohol as raw material through a series of oxidation-Henry reaction, which is more challenging than the traditional construction of carbonyl C(sp2)-C(sp3) bond. The conversion method of alcohol to beta-nitro alcohol promoted by alkali developed in the present application has mild reaction conditions, simple operation, low requirement for instrument equipment, low price and wide source of alcohol as reaction raw material, high yield of beta-nitro alcohol compound, wide substrate application range, and tolerance to most functional groups, which provides a new path for the synthesis of complex beta-nitro alcohol. DETAILED DESCRIPTION

[0016] The technical solutions of the present application will be described below in conjunction with the embodiments, obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the protection scope of the present application.

[0017] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as there is no conflict between them.

[0018] Example 1:

[0019]

[0020] In a 100 mL reaction bottle, 540 mg of benzyl alcohol (5 mmol), 20 mL of dimethyl sulfoxide, 2.44 g of nitromethane (40 mmol) and 1.04 g of potassium carbonate (7.5 mmol) were added, the rubber plug was plugged, and the reaction liquid was stirred at room temperature (25℃). Sulfuryl fluoride gas balloon was introduced into the reaction liquid through a long needle, and another short needle was inserted into the rubber plug to make the sulfuryl fluoride in the balloon flow with the air in the reaction system. After 5 minutes, the short needle was removed, and the reaction system was reacted at room temperature (25℃) for 12-15 hours. The reaction progress was detected by thin layer chromatography plate, and after the reaction was completed, the reaction liquid was extracted with water and dichloromethane (3×20 mL). The dichloromethane layer was dried with anhydrous sodium sulfate, filtered, and rotary evaporated. The residue was purified by silica gel column chromatography to obtain 1-phenyl-2-nitroethanol (802 mg, 96%).

[0021] 1H NMR (300 MHz, CDC13) δ ppm 7.34 - 7.43 (m, 5 H), 5.42 (dd, J=9.3, 1.8 Hz, 1 H), 4.59 (ddd, J=13.2, 9.6, 0.9 Hz, 1 H), 4.49 (ddd, J=13.5, 3.0, 0.9 Hz, 1 H), 2.91 (s, 1 H); 13 C NMR (75 MHz, CDC13) δ ppm 138.8, 129.7, 129.6, 126.6, 81.9, 71.6.

[0022] Example 2

[0023]

[0024] Into a 100 mL reaction flask, 570 mg of cyclohexylmethanol (5 mmol), 20 mL of dimethyl sulfoxide, 2.44 g of nitromethane (40 mmol), 1.04 g of potassium carbonate (7.5 mmol) were added, rubber stopper was plugged, stirred at room temperature (25 °C), sulfuric fluoride balloon was passed through a long needle into the reaction liquid, another short needle was inserted into the rubber stopper, so that the sulfuric fluoride in the balloon flowed with the air in the reaction system, after 5 min, the short needle was removed, the reaction system was reacted at room temperature (25 °C) for 12-15 hours. The reaction progress was detected by thin layer chromatography plate, after the reaction was completed, the reaction liquid was extracted with water and dichloromethane (3 x 20 mL), the dichloromethane layer was dried with anhydrous sodium sulfate, filtered, rotary evaporated, the residue was purified by silica gel column chromatography to obtain 2-nitro-1-cyclohexylethanol (813 mg, 94%).

[0025] 1 H NMR (400 MHz, CDC13) δ 4.42 (dd, J=13.1, 2.9 Hz, 1 H), 4.35 (dd, J=13.1, 8.9 Hz, 1 H), 4.03 (ddd, J=11.6, 5.8, 2.9 Hz, 1 H), 2.48 (d, J=5.2 Hz, 1 H), 1.81 - 1.67 (m, 3 H), 1.67 - 1.54 (m, 2 H), 1.40 (m, 1 H), 1.26 - 0.95 (m, 5 H). 13 C NMR (100 MHz, CDC13) δ 79.4, 73.0, 41.5, 28.9, 28.1, 26.2, 26.0, 25.9.

[0026] Example 3

[0027]

[0028] Into a 100 mL reaction flask, add 630 mg of 4-fluorobenzyl alcohol (5 mmol), 20 mL of dimethylsulfoxide, 2.44 g of nitromethane (40 mmol) and 1.04 g of potassium carbonate (7.5 mmol), seal the rubber stopper, stir at room temperature (25 °C), pass the sulfuryl fluoride gas balloon through a long needle into the reaction liquid, insert another short needle into the rubber stopper, so that the sulfuryl fluoride in the balloon flows with the air in the reaction system, after 5 min, remove the short needle, the reaction system is reacted at room temperature (25 °C) for 12-15 hours. The reaction progress is detected by thin layer chromatography plate, after the reaction is completed, the reaction liquid is extracted with water and dichloromethane (3x20 mL), the dichloromethane layer is dried with anhydrous sodium sulfate, filtered, rotary evaporated, the residue is purified by silica gel column chromatography to obtain 1-(4-fluorophenyl)-2-nitroethanol (870 mg, 94%).

[0029] 1 H NMR (300 MHz, CDC13) δ ppm 7.31-7.49 (m, 2H), 7.00-7.20 (m, 2H), 5.45 (d, J = 9.1 Hz, 1H), 4.58 (dd, J = 13.5, 9.4 Hz, 1H), 4.49 (dd, J = 13.2, 3.5 Hz, 1H), 2.94 (d, J = 3.8 Hz, 1H); 13 C NMR (75 MHz, CDC13) δ 163.1 (d, J = 246.8 Hz), 134.1, 128.0 (d, J = 8.2 Hz), 116.2 (d, J = 21.8 Hz), 81.3, 70.5.

[0030] Example 4

[0031]

[0032] Into a 100 mL reaction flask, add 790 mg of 2-naphthaldehyde (5 mmol), 20 mL of dimethylsulfoxide, 2.44 g of nitromethane (40 mmol) and 1.04 g of potassium carbonate (7.5 mmol), seal the rubber stopper, stir at room temperature (25 °C), pass the sulfuryl fluoride gas balloon through a long needle into the reaction liquid, insert another short needle into the rubber stopper, so that the sulfuryl fluoride in the balloon flows with the air in the reaction system, after 5 min, remove the short needle, the reaction system is reacted at room temperature (25 °C) for 12-15 hours. The reaction progress is detected by thin layer chromatography plate, after the reaction is completed, the reaction liquid is extracted with water and dichloromethane (3x20 mL), the dichloromethane layer is dried with anhydrous sodium sulfate, filtered, rotary evaporated, the residue is purified by silica gel column chromatography to obtain 2-nitro-1-(naphthalen-2-yl)-ethanol (1.05 g, 97%).

[0033] 1H NMR (400 MHz, CDC13) δ 7.91 - 7.81 (m, 4H), 7.56 - 7.48 (m, 2H), 7.46 (dd, J = 8.6, 1.7 Hz, 1H), 5.61 (d, J = 9.3 Hz, 1H), 4.68 (dd, J = 13.4, 9.5 Hz, 1H), 4.58 (dd, J = 13.4, 3.1 Hz, 1H), 2.96 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 135.5, 133.5, 133.3, 129.2, 128.2, 127.9, 126.9, 126.8, 125.5, 123.3, 81.3, 71.3.

[0034] Example 5

[0035]

[0036] In a 100 mL reaction flask, 540 mg of benzyl alcohol (5 mmol), 20 mL of dimethyl sulfoxide, 3.00 g of nitrobenzene ethane (40 mmol) and 1.04 g of potassium carbonate (7.5 mmol) were added, a rubber plug was inserted, and the reaction was stirred at room temperature (25 °C). Sulfuryl fluoride gas was introduced into the reaction system through a long needle of a balloon, and a short needle was inserted into the rubber plug to generate a flow between the sulfuryl fluoride in the balloon and the air in the reaction system. After 5 minutes, the short needle was removed, and the reaction system was allowed to react at room temperature (25 °C) for 12-15 hours. The progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, the reaction solution was extracted with water and dichloromethane (3 x 20 mL). The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 2-nitro-1-phenylpropane (824 mg, 91%).

[0037] 1 H NMR (400 MHz, CDC13) δ 7.32 - 7.30 (m, 5H), 5.32 - 4.94 (m, 1H), 4.73 - 4.59 (m, 1H), 2.66 - 2.55 (m, 1H), 1.43 - 1.24 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 138.6, 128.9, 128.7, 126.1, 87.6, 74.0, 12.2.

[0038] Example 6

[0039]

[0040] Into a 100 mL reaction flask, 920 mg of benzhydrol (5 mmol), 20 mL of dimethyl sulfoxide, 2.44 g of nitromethane (40 mmol), 1.04 g of potassium carbonate (7.5 mmol) were added, a rubber plug was put on, and the reaction was stirred at room temperature (25 °C). A balloon of sulfuric fluoride was connected to the reaction system through a long needle, and another short needle was inserted into the rubber plug to make the sulfuric fluoride in the balloon flow into the reaction system. After 5 min, the short needle was removed, and the reaction was allowed to proceed at room temperature (25 °C) for 12-15 h. The progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was extracted with water and dichloromethane (3 x 20 mL). The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give 2-nitro-1,1-diphenylethane (1.07 g, 88%).

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.46-7.22 (m, 10H), 5.52 (s, 1H), 5.18 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ 145.0, 129.2, 128.2, 126.2, 91.1, 79.5.

[0042] In combination with Examples 1-6, the synthetic method designed in the present application can realize the conversion of alcohol compounds to β-nitro alcohol under alkaline conditions, and has the advantages of mild reaction conditions, high reaction efficiency, simple operation, and wide applicability, thereby providing a new path for the synthesis of β-nitro alcohol.

[0043] Although the embodiments of the present application have been disclosed as above, they are not limited to the applications listed in the specification and the embodiments, and can be fully applied to various fields suitable for the present application, and additional modifications can be easily realized by those skilled in the art. Therefore, the present application is not limited to specific details, but is within the general concept defined by the claims and the equivalent scope.

Claims

1. A method for one-pot synthesis of β-nitro alcohols from alcohol compounds as starting materials, characterized in that, is a β-nitro alcohol compound obtained by using alcohol and nitro compound as raw materials, reacting at room temperature under the action of sulfuryl fluoride gas and alkaline catalyst, and separating and purifying; the β-nitro alcohol compound has the following structural formula wherein R1, R2 are phenyl, substituted phenyl, heterocyclic aryl, condensed ring aryl, substituted condensed ring aryl, alkyl or hydrogen atom; R3, R4 are aryl, hydrogen atom or alkyl. The alcohol has the following structural formula: wherein R1, R2 is phenyl, substituted phenyl, heterocyclic aryl, fused ring aryl, substituted fused ring aryl, alkyl or hydrogen atom; The nitro compound has the following structural formula: wherein R3, R4 are aryl, hydrogen atom or alkyl group; The base catalyst is potassium carbonate, sodium hydroxide, DABCO, DMAP, sodium hydroxide or sodium methoxide.

2. The method for synthesizing β-nitro alcohol from an alcohol compound as a starting material in one pot according to claim 1, wherein, The reaction is carried out in an organic solvent, which is acetonitrile, dimethyl sulfoxide, dichloromethane, methanol, acetonitrile, tetrahydrofuran or ethanol. ​ 3. The method according to claim 1, wherein the alcohol compound is used as a starting material to synthesize the β-nitro alcohol in one pot. The molar ratio of the alcohol to the nitro compound is 1:1-10.

4. The method for synthesizing β-nitro alcohol from an alcohol compound in one pot according to claim 1, wherein the alcohol compound is represented by the following formula (1) : ###0001### (1) and the reaction is carried out in the presence of a base and a nitrosating agent. The step of separation and purification is as follows: after the reaction is completed, the reaction solution is extracted with water and dichloromethane, the obtained dichloromethane layer is dried with anhydrous sodium sulfate, filtered, and rotary evaporated, and the residue is purified by silica gel column chromatography.

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