阅读说明：本技术 一种芳基酚类或芳基醚类衍生物的硝化方法 (Nitration method of aryl phenol or aryl ether derivative ) 是由 邓清海 李思源 关振宇 于 2019-08-28 设计创作，主要内容包括：本发明涉及一种芳基酚类或芳基醚类衍生物的硝化方法,在空气下,将芳基酚类或者芳基醚类化合物、硝酸盐、三甲基氯硅烷(TMSCl)和铜盐在乙腈溶液中,室温下搅拌,同时通过TLC点板监测反应程度,待底物消耗完全后,然后将混合物用旋转蒸发器移除溶剂后,通过硅胶柱纯化,即可得到硝基烯烃衍生物。同时通过对硝酸盐当量的控制,可以实现底物选择性单硝化或双硝化。与现有技术相比,本发明的硝化方法避免使用强酸物质,反应条件温和、产率高、底物适用范围广,放大反应后反应活性未出现明显衰减,仍获得优秀的收率,具有明显的工业应用价值。(The invention relates to a nitration method of aryl phenols or aryl ether derivatives, which comprises the steps of stirring aryl phenols or aryl ether compounds, nitrate, trimethylchlorosilane (TMSCl) and copper salt in acetonitrile solution at room temperature, monitoring the reaction degree through a TLC point plate, removing a solvent from a mixture by using a rotary evaporator after a substrate is completely consumed, and purifying through a silica gel column to obtain the nitroolefin derivatives. Meanwhile, by controlling the equivalent of the nitrate, the selective mono-nitrification or double-nitrification of the substrate can be realized. Compared with the prior art, the nitration method avoids using strong acid substances, has mild reaction conditions, high yield and wide substrate application range, does not obviously attenuate the reaction activity after amplification reaction, still obtains excellent yield and has obvious industrial application value.)

1. A nitration method of aryl phenol or aryl ether derivatives is characterized in that phenol or ether compounds react in a copper salt, a nitrate, trimethylchlorosilane (TMSCl) and acetonitrile system to prepare nitrophenol or ether derivatives,

the structural formula of the phenol or ether compound is shown as a formula 1, and the structural formula of the nitrophenol or ether derivative is shown as a formula 2:

wherein R is¹、R²And R³Independently selected from hydrogen, aromatic hydrocarbon group, aliphatic hydrocarbon group, substituted aliphatic hydrocarbon group, halogen or amide.

2. The nitration process of an aryl phenol or aryl ether derivative according to claim 1, comprising the steps of:

(1) in the air atmosphere, putting a phenol or ether compound, nitrate, trimethylchlorosilane (TMSCl) and copper salt into acetonitrile, and stirring at room temperature for reaction for 2-24 h;

(2) the reaction degree is monitored by TLC spot plate, when the phenol or ether compound is completely consumed, the mixture is purified by silica gel column after the solvent is removed by a rotary evaporator, and the nitrophenol or ether derivative is obtained.

3. The nitration method of an aryl phenol or aryl ether derivative according to claim 2, wherein the molar ratio of the phenol or ether compound to the nitrate is 1: 1.05-2.4.

4. The method for nitrating an aryl phenol or aryl ether derivative according to claim 2 or 3, wherein the nitrate is guanidine nitrate, lithium nitrate, sodium nitrate, lithium nitrate, or silver nitrate.

5. The nitration process of an aryl phenol or aryl ether derivative according to claim 2, wherein the molar ratio of the phenol or ether compound to TMSCl is 1: 1.1-4.

6. The nitration process of an aryl phenol or aryl ether derivative according to claim 2, wherein the molar ratio of the phenol or ether compound to the copper salt is 1: 0.01-0.1.

7. The method for nitration of an aryl phenol or aryl ether derivative according to claim 2 or 6, wherein said copper salt is selected from one or more of cuprous chloride, cupric nitrate trihydrate, cupric sulfate pentahydrate, copper powder, cupric oxide, cuprous oxide, copper trifluoromethanesulfonate or cupric acetate.

8. The nitration process of an aryl phenol or an aryl ether derivative according to claim 1 or 2, wherein the substituted benzene ring of said nitrophenol or ether derivative has the following structure: wherein R is²And R³Independently selected from hydrogen, alkyl, alkoxy, amido, ester, halogen, nitro, phenyl or alkenyl.

9. The method of claim 8, wherein the alkyl group comprises an alkyl group having a carbon number of C1-C10.

Technical Field

The invention relates to the field of organic synthesis, in particular to a nitration method of aryl phenol or aryl ether derivatives.

Background

The nitro-substituted aromatic compound is a very important intermediate and has wide application value in the fields of medical treatment, pesticides, dyes, explosives and the like. The traditional nitration reaction uses concentrated sulfuric acid and nitric acid mixed acid as a nitration reagent, and the method has the advantages of mature process, low cost, low atom utilization rate, serious environmental pollution, more byproducts, violent reaction and huge potential safety hazard.

In recent years, numerous chemists have been working on the optimization of the nitration of aromatic hydrocarbons. In addition to the use of nitric acid with strong acidic substances such as concentrated sulfuric acid, trifluoromethanesulfonic acid or acetic anhydride as nitrating agents (Coon, c.l.; Blucher, w.g.; Hill, m.e.j.org.chem.1973,38, 4243-; also less corrosive^tBuNO₂And Crivello reagent (NH)₄NO₃TFAA) as nitrating agent (Wei, w. -t.; zhu, w. -m.; liang, H.Synlett.2017,28,2153-2158.Crivello, J.V.J.Org.chem. 1981,46, 3056-one 3060.). The common C-H nitration processes involving transition metal catalysis are most common with Rh and Pd as catalysts, whereas transition metals such as Zr, Ce, Bi and Fe achieve nitration of target substrates at high temperatures by superstoichiometric amounts of the corresponding nitrates (Xie, f.; Qi, z.; Li, x.angelw.chem., int.ed.2013,52,11862-11866. forms, b.p.; Buchwald, s.l.j.am.chem.soc.2009,131,12898-12899.Selvam, j.j.j.p.; Suresh, v.; venkatesswarru, y.tetrahedron let 2006,47,2507-2509.Wasinska, m.; kozewska, a.; skarki, j.synth.m.143, com.150. using these transition metal or otherwise expensive aryl-oriented processes with limited aromatic groups; and the reaction conditions need high temperature (such as 130 ℃), so that the method has potential safety risk, and most of the new methods are free radical process nitration reactions, the reactions are uncontrollable during amplification, the number of byproducts is large, the yield is seriously reduced, and the industrial application of the novel methods is limited. In 2019, Maruoka developed a method for completing electrophilic nitration of phenol by using trivalent iodine as a catalyst and using expensive aluminum nitrate at room temperature,however, the corresponding nitrated products are only obtained in relatively low yields (Kevin, A.J.O.; Maruoka, K.; org.Lett. 2019,21, 1315-1319.).

Chinese patent (CN101397293A) A green nitration method based on ionic liquid catalysis realizes the nitration of p-azole intermediate by taking acetyl nitrate as nitrating agent and ionic functional liquid as catalyst. Although the method has mild conditions, the product yield is high; but the substrate is limited seriously, the acetyl nitrate needs fuming nitric acid to be prepared in situ, and the preparation process of the ionic functional liquid is complicated. Chinese patent (CN108530242A) A direct nitration method of electron-rich aromatic hydrocarbon uses tert-butyl nitrite to nitrify the phenyl ether substance at room temperature, the method has mild reaction conditions, does not need a catalyst, but has lower product yield. Chinese patent (CN106045803B) A green biomimetic catalysis method for phenolic compounds uses metal-doped Al-MCM-41 molecular sieve, sodium nitrite and hydrogen peroxide to nitrify the phenolic compounds at normal temperature. The method is simple to operate and mild in condition, but when the sodium nitrite and hydrogen peroxide system is used for amplification production, the mixture of peroxide and nitration products has explosion risk, the atom economy is low, and the green chemical concept is not met. Chinese patent (CN107033005A) A nitration method of aromatic compounds, improves the production process, uses a hypergravity reactor to avoid side reaction caused by over-high local concentration, improves the nitration efficiency, but still uses a mixed acid system, is corrosive to equipment and has higher reaction temperature.

In conclusion, in the existing nitration technical scheme, a classic mixed acid nitration system has safety risk, and the reaction is violent and uncontrollable; the newly developed C-H nitration technology needs a guide group and noble metal catalysis, and meanwhile, the amplification reaction by-products are more; while direct nitration of substrates with transition metal nitrates generally requires high temperature environments, and most transition metal nitrates are relatively expensive (Zr (NO)₃)₄、Bi(NO₃)₃And the like) are not beneficial to actual production, and the nitration process by the nitro cations developed by the Maruoka has the defects of higher raw material cost, low yield and the like.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a nitration method of aryl phenol or aryl ether derivatives, aiming at breaking through the prior art and developing a new nitration method which is cheaper, efficient, green, safe and capable of being prepared in large quantity by utilizing common and easily-obtained cheap nitrate and not using noble metals.

The purpose of the invention can be realized by the following technical scheme:

the invention synthesizes the nitro-substituted phenol or anisole derivatives under mild conditions by taking low-cost nitrate as a nitro source and under milder conditions. Thereby avoiding the use of mixed acid or strong oxidizing system to reduce the corrosion of strong acid or strong oxidizing agent to the equipment and the danger of the traditional process of nitric acid during concentration. The nitro-substituted aryl phenol or aryl ether derivative is prepared in a safer, more efficient and greener way.

A nitration method of aryl phenol or aryl ether derivatives adopts phenol or phenyl ether compounds with a structure shown in a formula 1 to react in an acetonitrile system of copper salt, nitrate and trimethylchlorosilane (TMSCl) to generate nitrophenol or phenyl ether derivatives with a structure shown in a formula 2:

wherein R is¹、R²And R³Independently selected from hydrogen, aromatic hydrocarbon group, aliphatic hydrocarbon group, substituted aliphatic hydrocarbon group, halogen or amide.

The method specifically comprises the following steps:

(1) in a nitrogen atmosphere, stirring phenol or a phenylate compound with a structure shown in formula 1, nitrate, trimethylchlorosilane (TMSCl) and copper salt in acetonitrile at room temperature for 2-24 h; preferably, the reaction temperature is 25 ℃.

(2) The reaction degree was monitored by TLC plate, and after the completion of the consumption of the olefinic compound, the mixture was then purified by silica gel column after the solvent was removed by rotary evaporator to obtain the nitrophenol or the phenylate derivative.

Further, the mass ratio of the phenol or the phenylate compound to the nitrate is 1: 1.0.5-2.4; the mass ratio of the phenol or phenylate compound to the TMSCl is 1: 1.1-4; the mass ratio of the phenol or phenylate compound to the copper salt is 1: 0.01-0.1; preferably, the molar ratio of the phenol or the phenylate compound to the nitrate to the TMSCl is 1:1.4:2

The most preferred phenol or phenyl ether compounds are:

the corresponding mononitrated nitrophenol or phenyl ether derivatives produced are:

the corresponding generated double-nitration nitroolefin derivative is as follows:

the phenol or phenylate compound is subjected to nitration reaction, and the substituent on the benzene ring can be aliphatic hydrocarbon, aromatic hydrocarbon, halogen, amide and the like, but different substituents have different influences on the nitration reaction. The phenol compound containing the electron-donating substituent has a far better nitration effect than that of a phenol compound containing the electron-withdrawing substituent, but can be obtained with a yield more than medium, and meanwhile, the amide substituent can be subjected to a nitration reaction well, so that an excellent nitration yield can be obtained. The nitration method can also carry out amplification reaction of more than ten grams, can obtain corresponding products with higher yield, and has the possibility of industrial amplification.

Further, the copper salt includes cuprous chloride (CuCl), cupric chloride (CuCl)CuCl₂) Copper nitrate trihydrate (Cu (NO)₃·3H₂O), copper sulfate pentahydrate (CuSO)₄·5H₂O), copper powder (Cu), copper oxide (CuO), cuprous oxide (Cu)₂O), copper trifluoromethanesulfonate (Cu (OTf)₂) Or copper acetate (Cu (OAc)₂) One or more of (a). In a preferred embodiment, the copper salt is cuprous chloride (CuCl) or cupric chloride (CuCl)₂) Copper nitrate trihydrate (Cu (NO)₃)₂·3H₂O), copper sulfate pentahydrate (CuSO)₄·5H₂O), copper powder (Cu), copper oxide (CuO), cuprous oxide (Cu)₂O) and the like, almost all common copper salts in laboratories can catalyze the nitration reaction, the reaction effect is not very different, and moderate to excellent yield can be obtained. From the viewpoint of cost-economic availability, the preferred catalyst of the present invention is copper sulfate pentahydrate. In a more preferable scheme, the dosage of the copper sulfate pentahydrate is 1-10% of the molar weight of the phenol or phenylate compound. The catalyst consumption is reduced, the nitration reaction rate is slowed down, the reaction completion time is prolonged, and the target product can be obtained with high yield.

The nitrate is guanidine nitrate, lithium nitrate, sodium nitrate, lithium nitrate and silver nitrate. In the technical scheme of the invention, nitrate is used as a nitrate source, and guanidine nitrate, lithium nitrate, sodium nitrate, lithium nitrate, silver nitrate and the like can be used as the nitrate. The nitrate generates trimethylsilyl nitrate (TMSONO) under the action of trimethylchlorosilane₂) In Cu²⁺Under the action of (2), SET process occurs to generate NO₂ ⁺Then, the aryl phenol or ether derivative is attacked to carry out electrophilic substitution reaction, and a target product is obtained. A large number of experimental facts show that the nitrate can enable the nitration reaction of the invention to occur, the nitration efficiency is moderate and excellent, and the preferred nitrate is guanidine nitrate, and the nitration efficiency can reach 99 percent in consideration of comprehensive cost and nitration efficiency.

1)CNH(NH₂)₂·HNO₃+TMSCI→CNH(NH₂)₂·HCI+TMSONO₂

2)

3)

4)

The nitration of aromatic hydrocarbons can be divided into nitro radicals (. NO.) by the different classification of the nitro source₂) Or nitro cations (NO)₂ ⁺) Participating in nitration reaction. The existing metal-catalyzed aromatic hydrocarbon nitration reaction mainly adopts a nitro radical reaction, and the reactions have the defects of high cost, difficult amplification, pre-functionalization of aromatic hydrocarbon raw materials and the like. The aromatic hydrocarbon nitration reaction realized by industrially adopting a mixed acid system (nitric acid, sulfuric acid and other strong acids) is a nitration reaction with nitro cations participating in the nitration reaction, although the method is mature and has low cost, the nitric acid, the sulfuric acid and other strong acids are required to be used as nitration reagents, and only mixed products substituted at different positions can be obtained.

For the phenol or aryl ether compounds rich in electrons, nitration reaction with nitro positive ions can better prepare the nitrated derivatives thereof. But currently produces active NO₂ ⁺The method has limited processes except for mixed acid systems and expensive and difficult-to-prepare nitration reagents such as Crivello reagent and N-NO₂Besides the reagent, common inorganic nitrates such as sodium nitrate, potassium nitrate and guanidine nitrate are directly used as the nitration reagent, so that the nitration strategy is more economical and green.

The invention takes cheap and easily obtained sodium nitrate, guanidine nitrate or potassium nitrate as raw materials to generate active NO under a mild non-acid system₂ ⁺To obtain a nitrated product of a phenol or an ether in a high yield. Moreover, the reaction can be easily scaled up to the order of ten grams, and still yield the corresponding product in yields of over 90%. Therefore, the invention provides a nitration method with low cost and simple operation.

Compared with the prior art, the invention has the following advantages:

1) according to the technical scheme, copper salts such as blue vitriod and the like which are cheap and easy to obtain in the market are used as catalysts, and nitrate such as guanidine nitrate and the like are used as nitro sources, so that the nitration of phenol or phenyl ether compounds can be realized at room temperature, the yield is high, the preparation can be amplified by more than 10 g, and the method has potential industrial application value. Compared with the prior art, the method completely avoids using a mixed acid system or a nitrite and oxidant system, has cheap and easily obtained raw materials, mild reaction conditions, no need of high-temperature heating, greatly reduces the production cost, simplifies the production process, is beneficial to industrial production, and is safer, more economical and cheaper than the prior process for synthesizing nitrophenol or phenylate derivatives.

2) According to the invention, cheap and easily available nitrate is directly used as a nitro source for phenol or ether nitration, compared with a mixed acid system and a nitrite compound nitration system, no oxidant is required to be added, the method has the advantages of safety, low cost, environmental protection and the like, and simultaneously, the selective control of single nitration or double nitration of a substrate can be realized by controlling the equivalent weight of the nitrate; in theory, guanidine in the reaction system is only used as a nitro carrier, and can be recycled, so that the guanidine compound is more in line with the green chemical concept and has more economic benefits.

3) The invention uses common copper salt as the catalyst of the nitration reaction of aryl phenols or ether compounds, compared with the catalysts of iron-molecular sieve, ionic functional liquid and the like used in the prior art, the catalyst is cheap and easy to obtain, the production process is greatly optimized, and the production cost is reduced.

4) The invention realizes the direct nitration of phenol or phenyl ether compounds at room temperature, and compared with a mixed acid system or microwave system in the prior art, the invention has the advantages of difficult equipment corrosion, energy saving and environmental protection.

5) The technical scheme of the invention realizes the direct nitration synthesis of the nitrophenol or the phenylate derivative, has wide substrate application range and high yield, is easy to separate and purify the target product, simplifies the process steps and is beneficial to industrial production.

Detailed Description

The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.

All solvents, copper salts, nitrates, trimethylchlorosilane, and phenolic or etheric compounds used in the following examples were purchased from commercial sources.

All target compounds are NMR¹H) And (4) spectral data characterization.

All nitration reactions were carried out in 10mL open Schlenk tubes, if not otherwise specified.

The yields of the desired products in the following examples are isolated yields.