Method for synthesizing triarylmethane molecular skeleton from aromatic aldehydes and hydrazine hydrochloride substances

Abstract

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and a hydrazine hydrochloride substance. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and a hydrazine hydrochloride substance comprises the following steps: using the aromatic aldehyde and the hydrazine hydrochloride substance as reactants, firstly performing a Friedel-Crafts reaction in a first solvent, then distilling off the first solvent, adding zinc powder and a second solvent, and then performing a reduction reaction, and separating and purifying to obtain a triarylmethane molecular skeleton. The present invention uses a hydrazine hydrochloride substance to replace aniline to react with the aromatic aldehyde, synthesizing the triarylmethane molecular skeleton through a one-pot method, and the reaction conditions are mild, no Lewis acid is required, and the product is easy to separate and has a high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a triarylmethane molecular skeleton from aromatic aldehydes and hydrazine hydrochloride substances. Background Art

[0002] Triarylmethanes (TRAMs) are an important molecular skeleton that is widely found in various natural products, synthetic drugs and functional molecular skeletons, and can be used in drugs, functional materials, and especially imaging dyes. Among them, amino-containing triarylmethane molecular skeletons are the most widely used triarylmethane molecular skeleton structure due to their good performance brought by their unique structure.

[0003] The common amino-containing triarylmethane skeleton molecular structure is as follows:

[0004] .

[0005] Currently, arylation of diarylmethanes is the main route to synthesize triarylmethanes, but this method usually requires the synthesis of diarylmethyl precursors such as diarylmethyl halides or diarylmethanol derivatives.

[0006] A more direct and economical approach is to obtain triarylmethanes by three-component coupling of aromatic aldehydes with two arenes via a Lewis acid or Brønsted acid-catalyzed Friedel-Crafts reaction, which initially forms a diarylmethanol intermediate, which can further react with another arene molecule in one pot to generate the triarylmethane skeleton. Generally, electron-rich aromatic substrates such as phenol and anisole, as well as heteroaromatics such as indole, pyrrole, furan, and thiophene are the first choice for this reaction. Although aniline is a well-known electron-rich aromatic hydrocarbon, its application in this three-component coupling is very limited due to the high basicity and nucleophilicity of aniline, which may lead to the deactivation of Lewis acid or Brønsted acid catalysts. It is usually necessary to use a more hindered N,N-dialkylated aniline to avoid complexation between aniline and the catalyst. Moreover, the reaction is easily interrupted at the diarylmethanol intermediate stage, resulting in low product yields.

[0007] In addition, in existing reports, the three-component coupling reaction of aromatic aldehydes and aniline generally requires harsh conditions, such as microwaves, high temperature, high pressure, foreign reagents (ionic liquid solvents), extended reaction time, increased aniline equivalent ratio, etc. This not only increases the reaction cost and has poor economic efficiency, but also does not meet the environmental protection requirements of green chemical processes.

[0008] Therefore, it is necessary to provide a method for synthesizing an aminotriarylmethane molecular skeleton that has a wide substrate range, high reaction efficiency, good economy, and is conducive to reaction amplification and subsequent derivatization. Summary of the invention

[0009] In view of the shortcomings of the prior art, the present invention aims to provide a method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and a hydrazine hydrochloride substance, wherein a hydrazine hydrochloride substance is used to replace aniline and the aromatic aldehyde, and the triarylmethane molecular skeleton is synthesized by a one-pot method. The reaction conditions are mild, no Lewis acid is required, and the product is easy to separate and the yield is high.

[0010] The technical purpose of the present invention is achieved through the following technical solutions:

[0011] A method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and a hydrazine hydrochloride substance comprises the following steps: taking the aromatic aldehyde and the hydrazine hydrochloride substance as reactants, firstly carrying out a Friedel-Crafts reaction in a first solvent, then distilling off the first solvent, adding zinc powder and a second solvent, and then carrying out a reduction reaction, and obtaining the triarylmethane molecular skeleton through separation and purification.

[0012] In the present invention, the structural formula of the aromatic aldehyde is:

[0013]

[0014] Among them, R 1 It is one of 4-methyl, 4-hydroxy, 4-methoxy, 4-oxyphenyl, 4-oxytrifluoromethyl, 4-thiomethyl, 4-tert-butyl, 4-ethyl, 4-phenyl, 4-hydrogen, 4-cyano, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-methylformyl, 4-methanesulfonyl, 3-methoxy, 3-methyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-methoxy, 2-methyl, 2-fluoro, 2-chloro, 2-bromo, 3,5-dimethyl, 3,5-dimethoxy, 2-hydroxy, 3-methyl, and 2,4-dichloro.

[0015] In some embodiments, the benzene ring in the aromatic aldehyde structure can also be replaced by one of a 2,3-dihydrobenzofuran ring, a thiophene ring, a naphthalene ring, and a phenanthrene ring.

[0016] Preferably, the aromatic aldehyde is methylbenzaldehyde, p-hydroxybenzaldehyde, p-methoxybenzaldehyde, p-phenoxybenzaldehyde, p-oxytrifluoromethylbenzaldehyde, p-methylthiobenzaldehyde, p-tert-butylbenzaldehyde, p-ethylbenzaldehyde, p-phenylbenzaldehyde, benzaldehyde, p-cyanobenzaldehyde, p-trifluoromethylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodobenzaldehyde, methyl p-formylbenzoate, p-methylsulfonylbenzaldehyde, m-methoxybenzaldehyde, m-methylbenzaldehyde, m-trifluoromethylbenzaldehyde, One of methylbenzaldehyde, m-fluorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, o-methoxybenzaldehyde, o-methylbenzaldehyde, o-fluorobenzaldehyde, o-chlorobenzaldehyde, o-bromobenzaldehyde, naphthalene-1-carboxaldehyde, naphthalene-2-carboxaldehyde, phenanthrene-9-carboxaldehyde, 2,3-dihydrobenzofuran-5-carboxaldehyde, 3,5-dimethylbenzaldehyde, 3,5-dimethoxybenzaldehyde, 2,4-dichlorobenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde-1-carboxaldehyde, 2-thiophenecarboxaldehyde, and 3-thiophenecarboxaldehyde.

[0017] In the present invention, the hydrazine hydrochloride substance is an equimolar ratio of nitrogen methyl phenyl hydrazine ( ) and HCl, or a substance of the following structural formula:

[0018] ,

[0019] Among them, R 2 It is one of 4-hydrogen, 2-methyl, 2-ethyl, 2,6-dimethyl, and 3-methyl.

[0020] Preferably, the hydrazine hydrochloride substance is one of the following substances: phenylhydrazine hydrochloride, o-methylphenylhydrazine hydrochloride, o-ethylphenylhydrazine hydrochloride, 2,6-dimethylphenylhydrazine hydrochloride, m-methylphenylhydrazine hydrochloride, and a mixture of nitrogen-methylphenylhydrazine and HCl.

[0021] The reaction process of the aromatic aldehyde and hydrazine hydrochloride substances is:

[0022] ;

[0023] or .

[0024] According to the above reaction process, the corresponding product triarylmethane molecular skeleton of the present invention can be the following substances: 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, 4-[bis(4-aminophenyl)methyl]phenol, 4-[(4-aminophenyl)(4-methoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)[4-(phenyloxy)phenyl]methyl]aniline, 4-[(4-aminophenyl){4-[(trifluoromethyl)oxy]phenyl}methyl]aniline, 4-[(4-aminophenyl)[4-(methylthio)phenyl]methyl]aniline, 4-[(4-aminophenyl)(4-tert-butylphenyl)methyl]aniline, 4-[(4-aminophenyl)(4-ethylphenyl)methyl]aniline , 4-[(4-aminophenyl)(1,1'-biphenyl)methyl]aniline, 4-[(4-aminophenyl)phenylmethyl]aniline, 4-[(4-aminophenyl)[4-(cyano)phenyl]methyl]aniline, 4-[(4-aminophenyl)[4-(trifluoromethyl)phenyl]methyl]aniline, 4-[(4-aminophenyl)(4-fluorophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-iodophenyl)methyl]aniline, 4-[bis(4-aminophenyl)methyl]benzoic acid methyl ester, 4-[(4-aminophenyl)[4-(methyldioxy-λ6- 4-[(4-aminophenyl)(3-methoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)(3-methylphenyl)methyl]aniline, 4-[(4-aminophenyl)[3-(trifluoromethyl)phenyl]methyl]aniline, 4-[(4-aminophenyl)(3-fluorophenyl)methyl]aniline, 4-[(4-aminophenyl)(3-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(3-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(2-methoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)(2-methylphenyl)methyl]aniline, 4-[(4-aminophenyl)(2-fluorophenyl)methyl]aniline, 4-[(4- aniline, 4-[(4-aminophenyl)(2-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(2-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(naphthalen-1-yl)methyl]aniline, 4-[(4-aminophenyl)(naphthalen-2-yl)methyl]aniline, 4-[(4-aminophenyl)(phenanthren-9-yl)methyl]aniline, 4-[(4-aminophenyl)(2,3-dihydro-1-benzofuran-5-yl)methyl]aniline, 4-[(4-aminophenyl)(3,5-dimethylphenyl)methyl]aniline, 4-[(4-aminophenyl)(3,5-dimethoxyphenyl)methyl]aniline, 6-[bis(4-aminophenyl)methyl]-2-methoxyphenol, 4-[(4-aminophenyl)(2,4-[(4-aminophenyl)(thiophen-2-yl)methyl]aniline, 4-[(4-aminophenyl)(thiophen-3-yl)methyl]aniline, 4-[(4-amino-3-methylphenyl)(4-methylphenyl)methyl]-2-methylaniline, 4-[(4-amino-3-methylphenyl)(4-methylphenyl)methyl]-2-ethylaniline, 4-[(4-amino-2-methylphenyl)(4-methylphenyl)methyl]-3-methylaniline, 4-[(4-amino-3,5-dimethylphenyl)(4-methylphenyl)methyl]-2,6-dimethylaniline, methyl(4-{[4-(methylamino)phenyl](4-methylphenyl)methyl}phenyl)amine.

[0025] In the present invention, based on the molar amount of benzene rings contained in the hydrazine hydrochloride substance, the molar ratio of the hydrazine hydrochloride substance to the aromatic aldehyde is 1:1-1.5, preferably 1:1.1, and most preferably 1:1; the molar ratio of the aromatic aldehyde to the zinc powder is 1:5-20, preferably 1:10-20, and most preferably 1:10.

[0026] When performing the Friedel-Crafts reaction, the first solvent is one of ethanol, isopropanol, hexafluoroisopropanol, methanol, tetrahydrofuran, and acetic acid, preferably methanol or ethanol, and most preferably methanol; the amount of the first solvent is not required, and generally, the volume of the first solvent corresponding to each 1 mol of aromatic aldehyde should not be less than 2 L.

[0027] The Friedel-Crafts reaction time is not less than 30 min, preferably 30-45 min; the Friedel-Crafts reaction temperature is 40-65°C.

[0028] When the reduction reaction is carried out, the second solvent is acetic acid. The amount of the second solvent is not required. Generally, the volume of the second solvent corresponding to 1 mol of aromatic aldehyde should not be less than 10 L.

[0029] The reduction reaction time is not less than 4 hours, preferably 4-8 hours, and the reduction reaction temperature is 20-30° C. The reduction reaction is a NN bond breaking reaction of the triarylmethane skeleton molecule containing a hydrazone structure.

[0030] The structural formula of hydrazine hydrochloride is For example, the reaction principle of the aromatic aldehyde and hydrazine hydrochloride is as follows:

[0031] .

[0032] From the above reaction principle, it can be seen that in the first step of the reaction, hydrazine hydrochloride substances and aromatic aldehydes first undergo Schiff base reaction to generate hydrazone compounds, and then the remaining aromatic aldehydes undergo Friedel-Crafts reaction with hydrazone compounds to obtain triarylmethane molecular skeleton intermediates; wherein the generation of hydrazone compounds plays a key role in the reaction, and the present invention has found through a large number of studies and experiments that methanol as a proton solvent is the best solvent for the generation of hydrazone compounds, followed by ethanol, and the above solvents are also conducive to the Friedel-Crafts reaction; in addition, when aromatic aldehydes and hydrazone compounds undergo Friedel-Crafts reaction to obtain triarylmethane molecular skeleton intermediates, acid activation is required, and the use of hydrazine hydrochloride substances as reaction raw materials can activate the reaction. In the second step reaction, zinc powder is used as a reducing agent in combination with acetic acid. Under the acidic conditions of acetic acid, zinc powder can produce a variety of reducing substances such as hydrogen atoms, hydrogen gas, and single electrons. These reducing substances are difficult to produce in other solvents. Zinc powder reduces the hydrazone structure in the triarylmethane molecular skeleton intermediate under the acidic conditions of acetic acid to achieve N-N bond breaking, thereby obtaining the triarylmethane molecular skeleton. The reaction conditions are mild and the selectivity is high.

[0033] After the reduction reaction is completed, a saturated sodium bicarbonate solution is added to quench the reaction, and then separation and purification are performed.

[0034] During separation and purification, an extractant is first used for extraction, and then the extractant is removed by distillation, and then purified by silica gel column chromatography to obtain a triarylmethane molecular skeleton.

[0035] The extractant is preferably ethyl acetate; the eluent used in the silica gel column chromatography purification is preferably a mixture of ethyl acetate and petroleum ether in a volume ratio of 2:1.

[0036] Furthermore, in order to obtain a product with higher purity, when using an extractant for extraction, ethyl acetate can be used for extraction first, the organic phase can be collected, and then back-extracted with saturated brine, and dried with anhydrous sodium sulfate, filtered, and then the next distillation operation can be performed.

[0037] The triarylmethane molecular skeleton synthesized by the present invention can be used to prepare the following derivatives through a derivatization reaction:

[0038]

[0039] 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline salt,

[0040]

[0041] (4-{[4-(dimethylamino)phenyl](4-methylphenyl)methyl}phenyl)dimethylamine,

[0042]

[0043] 4-{[4-(benzylamino)phenyl](4-methylphenyl)methyl}aniline,

[0044]

[0045] Benzyl(4-{[4-(benzylamino)phenyl](4-methylphenyl)methyl}phenyl)amine,

[0046]

[0047] 2-methylpropan-2-yl ({4-[(4-aminophenyl)(4-methylphenyl)methyl]phenyl}amino)methanoate,

[0048]

[0049] N-{4-[(4-methylphenyl)[4-(phenylamino)phenyl]methyl]phenyl}aniline,

[0050]

[0051] 1-[Bis(4-chlorophenyl)methyl]-4-methylbenzene.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] (1) The present invention uses aromatic aldehydes and hydrazine hydrochloride substances as raw materials to synthesize triarylmethane molecular skeletons through a one-pot process, wherein the alkalinity of hydrazine hydrochloride substances is weaker than that of aniline, the reaction conditions are milder, the reaction compatibility is good, and the catalyst deactivation can be avoided; in addition, aromatic aldehydes and hydrazine hydrochloride substances can form more stable aromatic hydrazone compounds in situ, and aromatic hydrazone compounds have weak electron donating properties and can maintain high Friedel-Crafts reaction activity with aromatic aldehydes. At the same time, since their volume is larger than that of aniline, the ortho / para regioselectivity of the reaction can be improved;

[0054] (2) The reaction conditions of the present invention are simple and mild, and no Lewis acid needs to be introduced. The reaction conditions of the present invention are applicable to a wide range of substrates. The product is easy to separate and has a high yield, which is conducive to industrial production.

[0055] (3) The -NH2 group in the triarylmethane molecular skeleton synthesized in the present invention can be further derivatized to obtain various derivatives of molecules containing the triarylmethane skeleton. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is the H NMR spectrum of the product of Example 1 of the present invention;

[0057] Figure 2 This is the NMR carbon spectrum of the product of Example 1 of the present invention;

[0058] Figure 3 This is the H NMR spectrum of the product of Example 2 of the present invention;

[0059] Figure 4 This is the NMR carbon spectrum of the product of Example 2 of the present invention;

[0060] Figure 5 This is the H NMR spectrum of the product of Example 3 of the present invention;

[0061] Figure 6 This is the NMR carbon spectrum of the product of Example 3 of the present invention;

[0062] Figure 7 This is the H NMR spectrum of the product of Example 4 of the present invention;

[0063] Figure 8 This is the NMR carbon spectrum of the product of Example 4 of the present invention;

[0064] Fig. 9 This is the NMR fluorine spectrum of the product of Example 4 of the present invention;

[0065] Fig.10 This is the H NMR spectrum of the product of Example 5 of the present invention;

[0066] Fig.11 This is the NMR carbon spectrum of the product of Example 5 of the present invention;

[0067] Fig.12 This is the H NMR spectrum of the product of Example 6 of the present invention;

[0068] Fig.13 This is the NMR carbon spectrum of the product of Example 6 of the present invention;

[0069] Fig.14 This is the H NMR spectrum of the product of Example 7 of the present invention;

[0070] Fig.15 This is the NMR carbon spectrum of the product of Example 7 of the present invention;

[0071] Fig.16 This is the H NMR spectrum of the product of Example 8 of the present invention;

[0072] Fig.17 This is the NMR carbon spectrum of the product of Example 8 of the present invention;

[0073] Fig.18 This is the H NMR spectrum of the product of Example 9 of the present invention;

[0074] Fig.19 This is the NMR carbon spectrum of the product of Example 9 of the present invention;

[0075] Fig. 20 This is the H NMR spectrum of the product of Example 21 of the present invention;

[0076] Fig.21 This is the NMR carbon spectrum of the product of Example 21 of the present invention;

[0077] Fig. 22 This is the H NMR spectrum of the product of Example 22 of the present invention;

[0078] Fig.23 This is the NMR carbon spectrum of the product of Example 22 of the present invention. DETAILED DESCRIPTION

[0079] The present invention is further described below with reference to the examples. The raw materials used in the examples, unless otherwise specified, are all commercially available conventional raw materials; the process methods used in the examples, unless otherwise specified, are all conventional methods in the art.

[0080] Example 1

[0081] This example synthesizes 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, the structural formula of which is as follows:

[0082]

[0083] The synthesis method is:

[0084] 0.3 mmol of p-methylbenzaldehyde, 0.3 mmol of phenylhydrazine hydrochloride and 1 ml of methanol were added to a round-bottom flask, and the temperature was raised to 65°C under magnetic stirring, and the reaction was carried out for 30 minutes. Then, the methanol was removed by rotary evaporation, and 3 mmol of zinc powder and 5 ml of acetic acid were added. The reaction was continued for 8 hours at 20°C and magnetic stirring. After the reaction was completed, 60 ml of saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phases were combined, back-extracted with 60 ml of saturated brine, dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by rapid silica gel column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 2:1) to obtain the product 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline with a yield of 90%.

[0085] The above product was qualitatively analyzed by NMR, dissolved in deuterated chloroform-d, and tested for hydrogen and carbon spectra, such as Figure 1-2 As shown, where:

[0086] 1H NMR (400 MHz, CDCl3): δ7.05 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 6.0Hz, 2H), 6.86 (dd, J = 6.4, 2.0 Hz, 4H), 6.55 (d, J = 8.4, 2.4 Hz, 4H), 5.28 (s, 1H), 3.50 (br, 4H), 2.28 (s, 3H).

[0087] 13 C NMR (100 MHz, CDCl3): δ144.5, 142.2, 135.4, 135.0, 130.2, 129.3, 128.9, 115.1, 54.9, 21.1.

[0088] HRMS (ESI) m / z: [M+H] + Calculate for C 20 H 21 N2 + 289.1699; found 289.1687.

[0089] Example 2

[0090] In this example, based on Example 1, p-tolualdehyde is replaced with an equal molar amount of p-ethylbenzaldehyde to synthesize 4-[(4-aminophenyl)(4-ethylphenyl)methyl]aniline, the structural formula of which is as follows:

[0091] .

[0092] The product yield was 94%, and the hydrogen and carbon spectra were as follows: Figure 3-4 As shown, where:

[0093] 1 H NMR (400 MHz, CDCl3): δ 7.13 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0Hz, 2H), 6.93 (d, J = 8.4 Hz, 4H), 6.63 (d, J = 8.4 Hz, 4H), 5.34 (s, 1H), 3.60 (br, 4H), 2.65 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

[0094] 13C NMR (101 MHz, CDCl3): δ144.4, 142.3, 141.7, 135.0, 130.2, 129.2,127.6, 115.1, 54.9, 28.4, 15.5.

[0095] HRMS (ESI) m / z:[M+H]+calcd for C 21 H 23 N2+303.1856; found 331.1821.

[0096] Comparative Example 1

[0097] This comparative example uses p-ethylbenzaldehyde, aniline and aniline hydrochloride as raw materials to synthesize 4-[(4-aminophenyl)(4-ethylphenyl)methyl]aniline, and the reaction process is as follows:

[0098] .

[0099] The synthesis method is:

[0100] Add 0.1 mmol of p-ethylbenzaldehyde, 0.35 mmol of aniline and 0.01 mmol of aniline hydrochloride into a pressure tube, heat the mixture to 150°C in an oil bath under nitrogen protection, and react for 2 h. Purify the reactant by rapid silica gel column chromatography (the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 2:1) to obtain the product 4-[(4-aminophenyl)(4-ethylphenyl)methyl]aniline with a yield of 60%.

[0101] Example 3

[0102] In this example, on the basis of Example 1, p-tolualdehyde is replaced with an equal molar amount of m-methoxybenzaldehyde to synthesize 4-[(4-aminophenyl)(3-methoxyphenyl)methyl]aniline, the structural formula of which is as follows:

[0103] ;

[0104] The product yield was 81%, and the hydrogen and carbon spectra were as follows: Figure 5-6 As shown, where:

[0105] 1H NMR (400 MHz, CDCl3): δ7.17 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4Hz, 4H), 6.75 – 6.68 (m, 2H), 6.67 (s, 1H), 6.59 (d, J = 8.4 Hz, 4H), 5.30 (s, 1H), 3.72 (s, 3H), 3.48 (br, 4H).

[0106] 13 C NMR (101 MHz, CDCl3): δ159.5, 146.8, 144.5, 134.6, 130.2, 129.0,121.9, 115.4, 115.1. 111.1, 55.2, 55.1.

[0107] HRMS (ESI) m / z: [M+H] + Calculate for C 20 H 21 N2O + 305.1648; found 305.1624.

[0108] Example 4

[0109] In this example, on the basis of Example 1, p-tolualdehyde was replaced with an equal molar amount of o-fluorobenzaldehyde to synthesize 4-[(4-aminophenyl)(2-fluorophenyl)methyl]aniline, the structural formula of which is as follows:

[0110] ;

[0111] The product yield was 82%, and the hydrogen spectrum, carbon spectrum and fluorine spectrum were as follows Figure 7-9 As shown, where:

[0112] 1 H NMR (400 MHz, CDCl3): δ7.13–7.06 (m, 2H), 6.98–6.91 (m, 3H), 6.84 (d, J = 8.4 Hz, 4H), 6.49 (d, J = 8.4 Hz, 4H), 5.60 (s, 1H), 3.47 (br, 4H).

[0113] 13C NMR (101 MHz, CDCl3): δ160.8 (d, J = 247.1 Hz), 144.9, 133.3, 132.4 (d, J = 14.4 Hz), 131.0 (d, J = 4.1 Hz), 130.2, 127.9 (d, J = 8.3 Hz), 123.9 (d, J = 3.6 Hz), 115.5, 115.2, 47.9 (d, J = 3.0 Hz).

[0114] 19F NMR (376 MHz, CDCl3): δ-116.5.

[0115] HRMS (ESI) m / z: [M+H] + Calculate for C 19 H 18 FN2 + 293.1449; found 293.1445.

[0116] Example 5

[0117] In this example, on the basis of Example 1, p-tolualdehyde is replaced with an equal molar amount of naphthalene-1-carboxaldehyde to synthesize 4-[(4-aminophenyl)(naphthalene-1-yl)methyl]aniline, the structural formula of which is as follows:

[0118] ;

[0119] The product yield was 83%, and the hydrogen and carbon spectra were as follows: Figure 10-11 As shown, where:

[0120] 1 H NMR (400 MHz, CDCl3): δ8.00 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.45 – 7.30 (m, 3H), 7.37-7.32 (m, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 4H), 6.59 (d, J = 8.4 Hz, 4H), 6.05 (s, 1H), 3.56 (br, 4H).

[0121] 13C NMR (101 MHz, CDCl3): δ144.5, 141.1, 134.5, 133.9, 132.0, 130.4,128.6, 127.3, 126.9, 125.9, 125.3, 125.2, 124.6, 115.2, 51.6.

[0122] HRMS (ESI) m / z: [M+H] + Calculate for C 23 H 21 N2 + 325.1699; found 325.1686.

[0123] Example 6

[0124] In this example, on the basis of Example 1, p-tolualdehyde is replaced with an equal molar amount of 3,5-dimethylbenzaldehyde to synthesize 4-[(4-aminophenyl)(3,5-dimethylphenyl)methyl]aniline, the structural formula of which is as follows:

[0125] ;

[0126] The product yield was 82%, and the hydrogen and carbon spectra were as follows: Figure 12-13 As shown, where:

[0127] 1 H NMR (400 MHz, CDCl3): δ6.91–6.86 (m, 4H), 6.81 (s, 1H), 6.72 (s,2H), 6.63 – 6.56 (m, 4H), 5.26 (s, 1H), 3.56 (br, 4H), 2.23 (s, 6H).

[0128] 13 C NMR (101 MHz, CDCl3): δ145.0, 144.3, 137.5, 135.0, 130.2, 127.7, 127.2, 115.1, 55.2, 21.4.

[0129] HRMS (ESI) m / z: [M+H] + Calculate for C 21 H 23 N2 + 303.1856; found 303.1842.

[0130] Example 7

[0131] In this example, based on Example 1, phenylhydrazine hydrochloride was replaced with an equimolar amount of o-methylphenylhydrazine hydrochloride to synthesize 4-[(4-amino-3-methylphenyl)(4-methylphenyl)methyl]-2-methylaniline, the structural formula of which is as follows:

[0132] ;

[0133] The product yield was 84%, and the hydrogen and carbon spectra were as follows: Figure 14-15 As shown, where:

[0134] 1 H NMR (400 MHz, CDCl3): δ7.10 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.0Hz, 2H), 6.87 (d, J = 2.0 Hz, 2H), 6.80 (dd, J = 8.0, 2.0 Hz, 2H), 6.75 (d, J= 8.0 Hz, 2H), 5.33 (s, 1H), 4.61 (br, 4H), 2.35 (s, 3H), 2.19 (s, 6H).

[0135] 13 C NMR (101 MHz, CDCl3): δ141.9, 140.3, 136.51 135.4, 131.5, 129.2,128.9, 127.8, 123.7, 116.1, 55.1, 21.0, 17.6.

[0136] HRMS (ESI) m / z: [M+H] + Calculate for C 22 H 25 N2 + 317.2012; found 317.1967.

[0137] Example 8

[0138] In this example, based on Example 1, phenylhydrazine hydrochloride was replaced with an equal molar amount of nitrogen methylphenylhydrazine (mixed with an equal molar equivalent of HCl) to synthesize methyl (4-{[4-(methylamino)phenyl](4-methylphenyl)methyl}phenyl)amine, the structural formula of which is as follows:

[0139] ;

[0140] The product yield is 80%, and the hydrogen and carbon spectra are as follows Figure 16-17 As shown, where:

[0141] 1H NMR (400 MHz, CDCl3): δ7.12 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0Hz, 2H), 6.98 (dd, J = 6.4, 2.0 Hz, 4H), 6.57 (dd, J = 6.4, 2.0 Hz, 4H), 5.37 (s, 1H), 3.59 (br, 2H), 2.85 (s, 6H), 2.36 (s, 3H).

[0142] 13 C NMR (101 MHz, CDCl3): δ147.5, 142.5, 135.3, 133.8, 130.1, 129.3,128.8, 112.3, 54.8, 30.9, 21.0.

[0143] HRMS (ESI) m / z: [M+H] + Calculate for C 22 H 25 N2 + 317.2012; found 317.1999.

[0144] Example 9

[0145] In this example, on the basis of Example 1, p-tolualdehyde is replaced with an equal molar amount of 3-thiophenecarboxaldehyde to synthesize 4-[(4-aminophenyl)(thiophen-3-yl)methyl]aniline, the structural formula of which is as follows:

[0146] ;

[0147] The product yield was 68%, and the hydrogen and carbon spectra were as follows: Figure 18-19 As shown, where:

[0148] 1 H NMR (400 MHz, CDCl3): δ7.24–7.20 (m, 1H), 6.91 (d, J = 8.0 Hz, 4H), 6.86 (dd, J = 4.8, 1.2 Hz, 1H), 6.71 – 6.68 (m, 1H), 6.60 (d, J = 8.4 Hz,4H), 5.28 (s, 1H), 3.52 (br, 4H).

[0149] 13C NMR (101 MHz, CDCl3): δ146.3, 144.6, 134.7, 129.7, 128.9, 125.2,122.3, 115.1, 51.0.

[0150] HRMS (ESI) m / z: [M+H] + Calculate for C 17 H 17 SN2 + 281.1107; found 281.1091.

[0151] Examples 10-20

[0152] Examples 10-20 Based on Example 1, the reaction conditions such as reaction temperature, reaction time, type of first solvent, and raw material ratio were changed to synthesize 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline to investigate the effects of the above factors on the yield of the reaction product. The reaction conditions and product yields are shown in Table 1.

[0153]

[0154] Embodiment 21

[0155] In this example, based on Example 1, a derivative of the product 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, N-{4-[(4-methylphenyl)[4-(phenylamino)phenyl]methyl]phenyl}aniline, is synthesized, and the structural formula is as follows:

[0156] ;

[0157] The synthesis method is:

[0158] A mixture of 0.2 mmol 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, 0.8 mmol phenylboric acid, 0.4 mmol Cu(OAc)2, 0.8 mmol triethylamine and 5 ml CH2Cl2 was reacted at room temperature for 24 h, the reaction mixture was poured into 60 ml water, extracted three times with 20 ml ethyl acetate, the organic layer was washed with 60 ml brine, dried over anhydrous MgSO4, filtered and concentrated, and the crude product was purified by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5) to obtain the derivative N-{4-[(4-methylphenyl)[4-(phenylamino)phenyl]methyl]phenyl}aniline with a yield of 85%.

[0159] The above product was qualitatively analyzed by NMR, dissolved in deuterated chloroform-d, and tested for hydrogen and carbon spectra, such as Figure 20-21 As shown, where:

[0160] 1 H NMR (400 MHz, CDCl3): δ7.33 (t, J = 7.6 Hz, 4H), 7.20 (d, J = 7.6Hz, 2H), 7.17 – 7.06 (m, 14H), 6.99 (t, J = 7.2 Hz, 2H), 5.70 (br, 2H), 5.50 (s, 1H), 2.42 (s, 3H).

[0161] 13 C NMR (101 MHz, CDCl3): 143.4, 141.7, 141.2, 137.3, 135.8, 130.3, 129.4, 129.3, 129.1, 120.8, 118.0, 117.5, 55.2, 21.1.

[0162] HRMS (ESI) m / z: [M+H] + Calculate for C 32 H 29 N2 + 441.2325; found 441.2325.

[0163] Embodiment 22

[0164] In this example, based on Example 1, a derivative of 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, 1-[bis(4-chlorophenyl)methyl]-4-methylbenzene, is synthesized, and the structural formula is as follows:

[0165] ;

[0166] The synthesis method is:

[0167] 0.2 mmol 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline was added to a mixture of 2 ml H2O and 5.5 ml HCl, and 2 ml of an aqueous solution containing 0.5 mmol NaNO2 was added dropwise at 0°C. The reaction was stirred at this temperature for 1 h, and then 0.5 mmol CuCl and 3 ml of concentrated hydrochloric acid were added at 0°C. The mixture was slowly heated to 70°C and reacted for 3 h. The reaction mixture was poured into 60 ml of water and extracted three times with 20 ml of ethyl acetate. The organic phase was washed with 60 ml of brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10) to obtain the derivative 1-[bis(4-chlorophenyl)methyl]-4-methylbenzene with a yield of 74%.

[0168] The above product was qualitatively analyzed by NMR, dissolved in deuterated chloroform-d, and tested for hydrogen and carbon spectra, such as Figure 22-23 As shown, where:

[0169] 1 H NMR (400 MHz, CDCl3): δ7.14 (d, J = 8.4 Hz, 4H), 7.00 (d, J = 7.6Hz, 2H), 6.91 (d, J = 8.4 Hz, 4H), 6.85 (d, J = 7.6 Hz, 2H), 5.34 (s, 1H),2.22 (s, 3H).

[0170] 13 C NMR (101 MHz, CDCl3): δ142.2, 140.0, 136.4, 132.4, 130.7, 129.3, 129.2, 128.6, 55.2, 21.1.

[0171] HRMS (ESI) m / z: [M+H] + Calculate for C 20 H 17 Cl2 + 327.0702; found 327.0656.

Claims

1. A method for synthesizing a triarylmethane molecular skeleton from aromatic aldehydes and hydrazine hydrochloride substances, characterized in that: Aromatic aldehyde and hydrazine hydrochloride are used as reactants, Schiff base reaction and Friedel-Crafts reaction are first carried out in a first solvent, then the first solvent is evaporated, zinc powder and a second solvent are added, and then reduction reaction is carried out, and the triarylmethane molecular skeleton is obtained after separation and purification; The structural formula of the aromatic aldehyde is: ， Among them, R 1 It is one of 4-methyl, 4-hydroxy, 4-methoxy, 4-oxyphenyl, 4-oxytrifluoromethyl, 4-thiomethyl, 4-tert-butyl, 4-ethyl, 4-phenyl, 4-hydrogen, 4-cyano, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-methylformyl, 4-methylsulfonyl, 3-methoxy, 3-methyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-methoxy, 2-methyl, 2-fluoro, 2-chloro, 2-bromo, 3,5-dimethyl, 3,5-dimethoxy, and 2,4-dichloro; The hydrazine hydrochloride substances are in an equal molar ratio. A mixture with HCl, or a substance of the following structural formula: ， Among them, R 2 One of 4-hydrogen, 2-methyl, 2-ethyl, 2,6-dimethyl, and 3-methyl; The triarylmethane molecular skeleton is the following substances: 4-[(4-aminophenyl)(4-methylphenyl)methyl]aniline, 4-[bis(4-aminophenyl)methyl]phenol, 4-[(4-aminophenyl)(4-methoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)[4-(phenyloxy)phenyl]methyl]aniline, 4-[(4-aminophenyl){4-[(trifluoromethyl)oxy]phenyl}methyl]aniline, 4-[(4-aminophenyl)[4-(methylthio)phenyl]methyl]aniline, 4-[(4-aminophenyl)(4-tert-butylphenyl)methyl]aniline, 4-[(4-aminophenyl)(4-ethylphenyl)methyl]aniline, 4-[(4-aminophenyl)(1,1'-biphenyl 4-[(4-aminophenyl)phenylmethyl]aniline, 4-[(4-aminophenyl)[4-(cyano)phenyl]methyl]aniline, 4-[(4-aminophenyl)[4-(trifluoromethyl)phenyl]methyl]aniline, 4-[(4-aminophenyl)(4-fluorophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(4-iodophenyl)methyl]aniline, 4-[bis(4-aminophenyl)methyl]benzoic acid methyl ester, 4-[(4-aminophenyl)[4-(methyldioxyylidene-λ6-thio)phenyl]methyl]aniline, 4-[(4-aminophenyl)[4-(trifluoromethyl)phenyl]methyl]aniline phenyl)methyl]aniline, 4-[(4-aminophenyl)(3-methylphenyl)methyl]aniline, 4-[(4-aminophenyl)[3-(trifluoromethyl)phenyl]methyl]aniline, 4-[(4-aminophenyl)(3-fluorophenyl)methyl]aniline, 4-[(4-aminophenyl)(3-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(3-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(2-methoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)(2-methylphenyl)methyl]aniline, 4-[(4-aminophenyl)(2-fluorophenyl)methyl]aniline, 4-[(4-aminophenyl)(2-chlorophenyl)methyl]aniline, 4-[(4-aminophenyl)(2-methoxyphenyl)methyl]aniline aniline, 4-[(4-aminophenyl)(2-bromophenyl)methyl]aniline, 4-[(4-aminophenyl)(3,5-dimethylphenyl)methyl]aniline, 4-[(4-aminophenyl)(3,5-dimethoxyphenyl)methyl]aniline, 4-[(4-aminophenyl)(2,4-dichlorophenyl)methyl]aniline, 4-[(4-amino-3-methylphenyl)(4-methylphenyl)methyl]-2-methylaniline, 4-[(4-amino-2-methylphenyl)(4-methylphenyl)methyl]-3-methylaniline, 4-[(4-amino-3,5-dimethylphenyl)(4-methylphenyl)methyl]-2,6-dimethylaniline, methyl(4-{[4-(methylamino)phenyl](4-methylphenyl)methyl}phenyl)amine; The first solvent is one of ethanol, isopropanol, hexafluoroisopropanol, methanol, tetrahydrofuran and acetic acid; and the second solvent is acetic acid.

2. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride substances according to claim 1, characterized in that: The aromatic aldehyde is one of p-hydroxybenzaldehyde, p-methoxybenzaldehyde, p-phenoxybenzaldehyde, p-oxytrifluoromethylbenzaldehyde, p-methylthiobenzaldehyde, p-tert-butylbenzaldehyde, p-ethylbenzaldehyde, p-phenylbenzaldehyde, benzaldehyde, p-cyanobenzaldehyde, p-trifluoromethylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodobenzaldehyde, methyl p-formylbenzoate, p-methylsulfonebenzaldehyde, m-methoxybenzaldehyde, m-methylbenzaldehyde, m-trifluoromethylbenzaldehyde, m-fluorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, o-methoxybenzaldehyde, o-methylbenzaldehyde, o-fluorobenzaldehyde, o-chlorobenzaldehyde, o-bromobenzaldehyde, 3,5-dimethylbenzaldehyde, 3,5-dimethoxybenzaldehyde, and 2,4-dichlorobenzaldehyde.

3. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride according to claim 1, characterized in that: The hydrazine hydrochloride substance is one of the following substances: phenylhydrazine hydrochloride, o-methylphenylhydrazine hydrochloride, o-ethylphenylhydrazine hydrochloride, 2,6-dimethylphenylhydrazine hydrochloride, m-methylphenylhydrazine hydrochloride, A mixture with HCl.

4. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride substances according to claim 1, characterized in that: Calculated on the molar amount of benzene rings contained in the hydrazine hydrochloride substances, the molar ratio of the hydrazine hydrochloride substances to the aromatic aldehyde is 1:1-1.5; the molar ratio of the aromatic aldehyde to the zinc powder is 1:5-20.

5. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride according to claim 4, characterized in that: Calculated by the molar amount of benzene rings contained in the hydrazine hydrochloride substances, the molar ratio of the hydrazine hydrochloride substances to the aromatic aldehyde is 1:1-1.1; the molar ratio of the aromatic aldehyde to the zinc powder is 1:10-20.

6. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride according to claim 1, characterized in that: The reduction reaction time is 4-8h, and the reduction reaction temperature is 20-30°C.

7. The method for synthesizing a triarylmethane molecular skeleton from an aromatic aldehyde and hydrazine hydrochloride according to claim 1, characterized in that: After the reduction reaction is completed, a saturated sodium bicarbonate solution is added to quench the reaction, and then separation and purification are performed.

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