KR20120034405A - Method of synthesis for aromatic bromides or aromatic chlorides from aromatic amines - Google Patents

Abstract

PURPOSE: A synthesizing method of aromatic bromides or aromatic chlorides is provided to have very simple and mild reaction condition, and to successfully synthesize aromatic bromides or aromatic chlorides from aromatic amine compounds with various substituents by using copper salt of catalytic amount. CONSTITUTION: A synthesizing method of aromatic bromides or aromatic chlorides in chemical formula 2: Ar-X from aromatic amine comprises: a step of adding sodium nitrite, alkyl nitride, p-TsOH, and ionic halogenide into aromatic an amine compound in chemical formula 1: Ar-HN2; a step of adding minimum amount of water not using organic solvent. And the ionic halogenide is selected from a group consisting of sodium bromide, potassium bromide, tetrabutyl ammonium bromide, and bezyltriethyl ammonium chloride.

Description

Method for synthesis of aromatic bromides or aromatic chlorides from aromatic amines

The present invention relates to a novel process for the synthesis of aromatic bromide or aromatic chloride from aromatic amines in high yield.

Diazonium salts have been reported to be highly reactive intermediates in various organic synthesis reactions, and because of their various usefulness, they are attracting attention not only synthetic chemistry but also industrially.

On the other hand, the present inventors studied a method for simple and effective diazotization-iodation of aromatic amines by using the properties of such diazonium salts. The diazotization and halogenation reactions are two-step one-pot processes involving the diazotization of amines which proceed by treatment of sodium nitrite or alkyl nitrite in the presence of acid and the subsequent reaction of halogenation reagents in the presence or absence of copper salts. .

Aromatic halides are known as important building blocks in organic synthesis reactions such as Suzuki cross-coupling and Heck-type reactions. One of the most popular methods for the synthesis of aromatic iodides from aromatic amines is the so-called Sandmeyer reaction. In addition, a successful method has been reported by Doyle for the halogenation of aromatic amines with alkyl nitrites in the presence of anhydrous copper salts (II) via substituted deamination reactions. Recently, a one-step method of iodinating aromatic derivatives using HI / KNO ₂ on DMSO solvent or KI / NaNO ₂ / p-TsOH on CH ₃ CN solvent has been reported.

However, the conventionally developed techniques cause environmental problems such as using an expensive organic solvent as a reaction solvent, using a large amount of strong acid, or using a large amount of harmful substances such as copper salts as reaction reagents. There is this. Therefore, there is a need for developing a method for effectively synthesizing aromatic halides.

Therefore, the present inventors brominated or chlorinated various aromatic amines through the diazotization-halogenation reaction in which arenediazonium tosylate salts are prepared as an intermediate by adding only a minimum amount of water to the reactants without using an organic solvent. The present invention has been accomplished by discovering that economical and effective aromatic bromide or aromatic chloride can be synthesized in one-pot.

Accordingly, it is an object of the present invention to provide a method for synthesizing aromatic bromide or aromatic chloride in high yield by a diazotization-halogenation reaction using a mechanical grinding method from an aromatic amine without using an organic solvent.

In order to achieve the above object, the present invention adds sodium nitrite or alkyl nitrite, p-TsOH and ionic halide to the aromatic amine compound of formula (I), and then adds a minimum amount of water without using an organic solvent The method of synthesize | combining the aromatic bromide or aromatic chloride of following formula (II) from an aromatic amine only by a mechanically thin method is provided.

Ar-NH ₂ (I)

Ar-X (II)

In one embodiment of the present invention, in the formula (I), Ar is phenyl, pyridyl, piperonyl, naphthyl, anthranyl, furyl, indolyl, quinolyl, isoquinolyl, benzoxazolyl, phenanthryl , Optionally substituted aryl and heteroaryl groups selected from the group consisting of pyrimidyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, amidazolyl, pyrazolyl, oxadiazolyl and dinodiazolyl, wherein any Substituents of may be selected from the group consisting of halogen, alkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, nitro, amino, alkylamino, carboxy, alkoxycarbonyl and hydroxy.

In one embodiment of the present invention, Ar in the formula (I) is 4-NO ₂ C ₆ H ₄ , 3-NO ₂ C ₆ H ₄ , 2-NO ₂ C ₆ H ₄ , 4-CNC ₆ H ₄ , 2-CNC ₆ H ₄ , 4-IC ₆ H ₄ , 4-BrC ₆ H ₄ , 4-ClC ₆ H ₄ , 4-OCH ₃ C ₆ H ₄ , 2-OCH ₃ C ₆ H ₄ And 4-NO ₂ -2-OCH ₃ C ₆ H ₃ and 2-NO ₂ -4-OCH ₃ C ₆ H ₃ .

In one embodiment of the present invention, X in formula (II) may be bromine or chlorine.

In one embodiment of the present invention, the ionic halide is sodium bromide (NaBr), potassium bromide (KBr), tetrabutyl ammonium bromide (TBAB) and benzyltriethyl ammonium chloride (Benzyltriethyl ammonium chloride; BTAC).

In one embodiment of the present invention, 0.5 to 2 equivalents of sodium nitrite or alkyl nitrite, 0.5 to 2 equivalents of ionic halide, and 0.5 to 2 equivalents of p-TsOH may be used with respect to 1 equivalent of the aromatic amine compound.

In one embodiment of the present invention, the small amount of water may be used in an amount of 0 to 1 ml of water per mmol of aromatic amine.

In one embodiment of the present invention, the reaction may be carried out for 5 to 60 minutes at 0 ~ 80 ℃.

In one embodiment of the present invention, a catalytic amount of 0.5 to 5.0 mol% copper (I) salt or copper (II) salt may be further added.

In one embodiment of the present invention, the copper (I) salt is CuBr or CuCl, the copper (II) salt may be CuBr ₂ or CuCl ₂ .

According to the present invention, the synthesis method is very simple, the reaction conditions are mild, and the copper bromide can be successfully synthesized in a high yield from the aromatic amine compound having various substituents using only a catalytic amount. It is effective in synthesizing aromatic halides and economics. Since it uses only a minimum amount of water without using organic solvents and strong inorganic acids, it is possible to minimize harmful wastes and thus provide an environmentally friendly and economical synthesis method. .

In the present invention, we have identified for the first time that arenediazonium tosylate salts can be used as new efficient reagents or intermediates in the halogenation of aromatic amines, and thus the present invention is formed as an intermediate through the diazotization-halogenation reaction. It is characterized by providing a novel and economical method for synthesizing aromatic halides from aromatic amine compounds using arenediazonium tosylate salts.

Arenediazonium tosylate salts are attracting attention not only for synthetic chemistry but also for industry because of their varying utility. The close multiple contact between the nitrogen atom in the diazonium cation and the oxygen atom in the tosylate anion affects the stability of these salts. In general, arenadiazonium salts have been reported as highly reactive intermediates in various organic synthesis reactions, and the remaining cations or subsequently reduced radicals of the azonium from which nitrogen molecules have been released are covalently bonded with carbon or other atoms.

In the present invention, "diazotization" refers to a reaction for obtaining a diazonium salt by reacting an aromatic primary amine with nitrous acid. The reaction was first discovered by P. Grease in 1858, after which a number of diazonium salts were studied. The amino group linked to the phenyl ring is converted to the diazonium salt. The diazonium salt is highly reactive and is called a diazo reaction. This reaction is an important reaction in the synthesis of organic compounds. In particular, diazo bonds capable of obtaining azo compounds are very important for preparing azo dyes.

In addition, in the present invention, "diazonium salt" refers to a compound obtained by diazotizing an aromatic primary amine with nitrous acid, which causes a diazo coupling reaction and is used in dyes and other organic synthetic compounds. Formula (ArN≡N) ⁺ X ^- (Ar is an aryl group, X ^- is an anion such as a halogen acid, sulfuric acid). P. Grease, who discovered the diazolation, thought that the benzenediazonium salt was a salt of the C ₆ H ₄ N ₂ group, and later claimed that FA kekulle had a structure of C ₆ H ₅ -N = N-X. Currently, the structure is described as a resonance hybrid of C ₆ H ₅ -N ⁺ ≡N ↔ C6H5-N = N ⁺ . It is chemically very unstable, releases nitrogen and decomposes even at room temperature to form phenol, and solids are easily exploded.

On the other hand, the method for synthesizing an aromatic halide from the aromatic amine according to the present invention is more specifically an organic solvent after adding sodium nitrite or alkyl nitrite, p-TsOH and ionic halide to the aromatic amine compound of formula (I) Aromatic bromide or aromatic chloride of the following formula (II) is synthesized only by adding a minimum amount of water and using a mechanical grinding method without using.

Ar-NH ₂ (I)

Ar-X (II)

Ar in formula (I) is phenyl, pyridyl, piperonyl, naphthyl, anthranyl, furyl, indolyl, quinolyl, isoquinolyl, benzooxazolyl, phenanthryl, pyrimidyl, oxazolyl, thiazolyl , Isooxazolyl, isothiazolyl, amidazolyl, pyrazolyl, oxadiazolyl and dinodiazolyl; and optionally substituted aryl and heteroaryl groups selected from the group consisting of: Wherein any substituent is selected from the group consisting of halogen, alkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, nitro, amino, alkylamino, carboxy, alkoxycarbonyl and hydroxy. More preferably Ar is an optionally substituted phenyl group and optional substituents are selected from halogen, nitro, cyano and methoxy groups.

In the formula (II), X is bromine or chlorine, and in the present invention, the aromatic halide is preferably bromide or chloride.

According to one embodiment of the present invention, as shown in Scheme 1, after adding a reactant such as p-toluenesulfonic acid (hereinafter referred to as 'p-TsOH'), nitrite, ionic halide, etc. starting substrate is lost when stirred with a pestle until the arene diazonium tosylate salt (ArN ₂ ^+, TsO ^-) as an intermediate via the diazotization reaction and are produced, such arene diazonium by reacting halogenating tosylate salt aromatic halogen Cargo can be synthesized in high yield.

<Scheme 1>

In Scheme 1, Ar of 1, 3, 4 is 4-NO ₂ C ₆ H ₄ , 3-NO ₂ C ₆ H ₄ , 2-NO ₂ C ₆ H ₄ , 4-CNC ₆ H ₄ , 2-CNC ₆ H ₄ , 4-IC ₆ H ₄ , 4-BrC ₆ H ₄ , 4-ClC ₆ H ₄ , 4-OCH ₃ C ₆ H ₄ , 2-OCH ₃ C ₆ H ₄ , 4-NO ₂ -2- One of OCH ₃ C ₆ H ₃ and 2-NO ₂ -4-OCH ₃ C ₆ H ₃ , 2 is sodium bromide (NaBr), potassium bromide (KBr), tetrabutyl ammonium bromide (Tetrabutyl ammonium bromide; TBAB) and benzyltriethyl ammonium chloride (BTAC), and X in 2, 3, 4 represents bromine or chlorine.

Since bromide and chlorides generally have lower nucleophilicity than iodide, the present invention takes this into account and only a minimal amount for the efficient bromination and chlorination when synthesizing aromatic halides from aromatic amine compounds It is preferable to proceed with the reaction using only water. At this time, the amount of water to be used is preferably used in 1 mL or less per 1 mmol of aromatic amine. As such, by using only a small amount of water without using an organic solvent or a strong inorganic acid, it is possible to minimize harmful wastes, thereby providing environmentally friendly synthesis technology.

In the present invention, p-TsOH is used as a reaction material, and an aromatic bromide and an aromatic chloride are synthesized in one-pot through the diazotization-halogenation reaction of an aromatic amine compound using nitrite and various halogenation reagents. In one embodiment of the present invention, the result of the synthesis reaction in the presence or absence of p-TsOH to confirm the effect of p-TsOH on the di-harmonization-halogenation reaction, the yield was very low in the absence of p-TsOH. Therefore, it was confirmed that p-TsOH is involved in the generation of arenadiazonium tosylate salts and effective halogenation reactions during the diazotization reaction of the present invention.

In addition, the diazotization-halogenation reaction in the present invention is preferably carried out at 0 ~ 80 ℃, if the reaction proceeds at a low temperature outside the temperature range may cause a problem that the reaction is not made completely, the temperature If the reaction proceeds at a temperature higher than the range may cause the occurrence of side reactions. In addition, the reaction time depends on the reaction temperature, it is good to proceed for 5 to 60 minutes depending on the temperature range.

In the present invention, the synthesis reaction is carried out using 0.5 to 2 equivalents of nitrite, 0.5 to 2 equivalents of halogenated reagent, and 0.5 to 2 equivalents of p-TsOH with respect to 1 equivalent of aromatic amine compound.

As the halogenating reagent used in the present invention, the bromination reagent may be sodium bromide (NaBr), potassium bromide (KBr) or tetrabutyl ammonium bromide (TBAB), and tetrabutyl ammonium bromide (TBAB). Tetrabutyl ammonium bromide (TBAB) is preferably used, and benzyltriethyl ammonium chloride (BTAC) is preferably used as the chlorination reagent. In the present invention, the nitrite may be used sodium nitrite or alkyl nitrite, preferably t-butyl nitrite.

In the present invention, the yield of the arrendiazonium tosylate may vary depending on the type of the aromatic amine compound, the type of nitrite, the type of halogenation reagent, the presence or absence of p-TsOH, the reaction temperature, the reaction time, and the like. Accordingly, the yield of aromatic bromide or chloride, which is the final product of the present invention, may vary. Therefore, desired yield can be achieved by appropriately adjusting the reaction conditions.

When a minimum amount of water is added under various reaction conditions and the aromatic amine compound is reacted using nitrite, p-TsOH, and a halogenation reagent, a large amount of nitrogen is rapidly generated and an aromatic halide is formed. The nature of free halogen ions in solution is a key factor in determining the rate of reaction, which is faster than chlorine ions, which bromine ions convert only to aryl chlorides after the reaction.

On the other hand, when comparing the final product of the diazotization-bromination reaction and the final product of the diazotization-chlorination reaction in the present invention, the yield of chloride is lower than bromide, which can be explained by the oxidation potential of the two halogen anions. In other words, the higher oxidation potential of Cl ⁻ makes electron transfer more difficult than Br ⁻ , resulting in low yield. Br ^- it can be a cause of low yields even lower chlorinated nucleophilic Saints ^- than Cl.

In addition, in the present invention, in order to slightly increase the yield, a catalytic amount of 0.5 to 5.0 mol% copper (I) salt or copper (II) salt may be further added. CuBr or CuCl can be used as such a copper (I) salt, and CuBr ₂ or CuCl ₂ can be used as a copper (II) salt.

Both Cu (I) salts and Cu (II) salts were effective in increasing the yield in the synthesis of aryl halides, and the Cu (I) and Cu (II) halides were not correlated with each other. Meanwhile, Cu (I) salts are known to play an important role in the Sandmeyer substitution reaction, but Cu (II) salts also act effectively in the present invention, and it can be assumed that they are reduced to Cu (I) during the reaction. Above all, in the present invention, it was confirmed that the Cu salt required for the reaction conditions for obtaining the excellent yield of the desired product was sufficient even in the small amount of the catalytic amount.

In the present invention, further purification of the aromatic halide obtained through the diazotization-halogenation reaction can be carried out to obtain a purer substance, and the purification method may be any purification method known in the art. It is OK and can be purified according to a known method. For example, it may be purified using column chromatography, but is not limited thereto.

According to the present invention, there is an advantage in that environmentally friendly synthesis of aromatic bromide or aromatic chloride from an aromatic amine compound in a high yield can be achieved in one step through a diazotization-halogenation reaction. In addition, the present invention can be uniformly applied to both aromatic amine compounds containing not only electron-withdrawing but also electron-donating groups.

Therefore, the aromatic bromide or aromatic chloride obtained through the present invention can be used as a useful material in the synthesis of bioactive materials and electronic materials or intermediates thereof.

Hereinafter, the present invention will be described in detail with reference to embodiments and drawings. However, these examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.

< Example  1>

Synthesis of Aromatic Bromide from Aromatic Amine Compounds

In order to synthesize aryl bromide, the present inventors have used aniline having various aromatic substituents as starting materials, and reacted with t-butyl nitrite, bromination reagent, copper salt and p-TsOH, and diazotized-brominated as shown in Scheme 2 below. By reaction, aryl bromide was synthesized. All types of reagents used in the synthesis were purchased from Aldrich and used without purification.

<Scheme 2>

Here, the inventors performed the synthesis by a total of two methods with different kinds of bromination reagents.

The reactants used in each method are as follows.

Method 1: t-butyl nitrite (t-BuONO), p-TsOH, CuBr ₂ , NaBr

Method 2: t-butyl nitrite (t-BuONO), p-TsOH, CuBr ₂ , TBAB

First, aniline (1.0 eq), p-TsOH (1.2 eq), t-butyl nitrite (1.2 eq), brominated reagent NaBr or TBAB (1.2 eq) and catalytic amount of CuBr ₂ (1 mol%) The reaction product was mixed with a small amount of water (0 to 0.3 ml / aniline 1 mmol) in a mortar and then stirred with a mortar for 15 to 20 minutes. At this time, it was immediately confirmed that N ₂ is generated. After the reaction was completed (identified by TLC), the solvent was removed using a rotary evaporator, the solvent was removed and the remaining solid was washed with water and extracted with CH ₂ Cl ₂ . The result was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. Next, the product was purified using column chromatography using hexane to produce a purer final product. At this time, dichloromethane was used as the elution solvent. In addition, the breaking point (Mp) of the final product was measured using MEL-TEMPII.

Bromination Yield of Aniline Example Kind of Ar Yield of Method 1 (%) Yield of Method 2 (%) Mp (℃) One 2-NO ₂ C ₆ H ₄ (1a) 55 71 38 ~ 39.5 (40 ^a ) 2 3-NO ₂ C ₆ H ₄ (1b) 58 77 51 ~ 52 (52 ^a ) 3 4-NO ₂ C ₆ H ₄ (1c) 65 87 123 ~ 124 (124 ^a ) 4 2-CNC ₆ H ₄ (1d) 42 68 52 ~ 54 (53 ~ 57 ^a ) 5 4-CNC ₆ H ₄ (1e) 54 82 109 ~ 111 (110 ^a ) 6 4-IC ₆ H ₄ (1f) 30 64 87 ~ 89 (89 ^a ) 7 4-BrC ₆ H ₄ (1 g) 16 60 82 ~ 84 (83 ^a ) 8 4-ClC ₆ H ₄ (1 h) 10 46 64 ~ 66 (64 ~ 67 ^a ) 9 2-MeOC ₆ H ₄ (1i) 0 44 oil (2 ^a ) 10 4-MeOC ₆ H ₄ (1j) 0 45 oil (9 ^a ) 11 4-NO ₂ -2-MeOC ₆ H ₄ (1k) 24 801 101-102 12 2-NO ₂ -4-MeOC ₆ H ₄ (1 l) 25 78 31-33 (32-33 ^a )

^a reference mp (Aldrich handbook of fine chemicals)

As a result, it was confirmed that the method 2 in which TBAB was added to the reaction mixture instead of NaBr as the bromination reagent was increased in the yield of the final product than in the method 1 in which NaBr was added. These results demonstrate that, unlike Method 1, Method 2 can be applied uniformly to aniline containing electron-donating groups as well as electron-withdrawing.

In addition, ¹ H-NMR analysis of the purely separated products obtained above are shown below. ¹ H NMR spectra were measured in CDCl ₃ using a Bruker 300 MHz spectrometer.

1- bromo -2- nitrobenzene (3a) . Yellow powder, mp: 38-40 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.83 (m, 1H, J = 7.2 Hz), 7.73 (m, 1H, J = 6.9 Hz), 7.43 (m, 2H) .

1- bromo- 3- nitrobenzene (3b) . Yellow powder, mp: 51-52 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.16 (d, 1H, J = 8.1 Hz), 7.81 (d, 1H, J = 7.8), 7.42 (t, 1 H, J = 8.1 Hz).

1- bromo -4- nitrobenzene (3c) . Creamy yellow solid, mp: 123-124 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, 2H, J = 6.9 Hz), 7.67 (d, 2H, J = 6.9 Hz).

2- bromobenzonitrile (3d) . Light brown solid, mp: 53-54 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ7.65 (m, 2H), 7.43 (m, 2H).

4- bromobenzonitrile (3e) . Pale yellow solid, mp: 109-111 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ7.62 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H, J = 8.4 Hz).

1- bromo -4- iodobenzene (3f) . Light brown solid, mp: 87-89 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.42 (d, 2H, J = 8.7), 7.11 (d, 2H, J = 8.4 Hz).

1,4- dibromobenzene (3 g) . White solid, mp: 82-84 ° C., mp: 82-84 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.34 (s, 4H).

1- bromo -4- chlorobenzene (3h) . Light yellow solid, mp: 64-66 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.40 (d, 2H, J = 8.7 Hz), 7.19 (d, 2H, J = 8.7 Hz).

1- bromo -2- methoxybenzene (3i) . White oil, 1H NMR (300MHz, CDCl ₃ ) δ7.52 (d, 1H, J = 7.8Hz), 7.25 (t, 1H, J = 7.2Hz), 6.84 (m, 2H), 3.87 (s, 3H) .

1- bromo -4- methoxybenzene (3j) . Pale yellow oil, 1 H NMR (300 MHz, CDCl ₃ ) δ 7.36 (d, 2H, J = 9.0 Hz), 6.66 (d, 2H, J = 9.0 Hz), 3.76 (s, 3H).

1- bromo -2- methoxy -4- nitrobenzene (3k) . Light creamy solid, mp: 101-102 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.71 (m, 3H), 3.99 (s, 3H).

1- bromo -4- methoxy -2- nitrobenzene (3l) . Brownish yellow solid, mp: 31-33 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.58 (d, 1H, J = 8.7 Hz), 7.35 (d, 1H, J = 3.0 Hz), 6.97 (m, 1H , J = 9.0 Hz), 3.84 (s, 3H).

Through the above results, it was confirmed that the aromatic bromide from the aromatic amine can be simply synthesized in a high yield through the diazotization-bromination reaction of the present invention.

< Example  2>

Synthesis of Aromatic Chlorides from Aromatic Amine Compounds

In order to synthesize an aryl chloride, the present inventors have used aniline having various aromatic substituents as starting materials, and reacted with t-butyl nitrite, chlorination reagent, copper salt, and p-TsOH, and diazotized-chlorination as shown in Scheme 3 below. By reacting, aryl chloride was synthesized.

<Scheme 3>

Here, the reactants used in the reaction are as follows: t-butyl nitrite (t-BuONO), p-TsOH, CuCl ₂ , BTAC

First, aniline (1.0 eq), p-TsOH (1.2 eq), t-butyl nitrite (1.2 eq), BTAC (1.2 eq) with a chlorination reagent and catalytic amount of CuCl ₂ (1 mol%) were mixed in a mortar. A small amount of water (0 to 0.3 ml / aniline 1 mmol) was added thereto, followed by stirring for 20 to 30 minutes with a pestle. At this time, it was immediately confirmed that N ₂ is generated. After the reaction was completed (identified by TLC), the solvent was removed using a rotary evaporator, the solvent was removed and the remaining solid was washed with water and extracted with CH ₂ Cl ₂ . The result was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. Next, the product was purified using column chromatography using hexane to produce a purer final product. At this time, dichloromethane was used as the elution solvent. In addition, the breaking point (Mp) of the final product was measured using MEL-TEMPII.

Chlorination yield of aniline Example Kind of Ar yield(%) Mp (℃) One 2-NO ₂ C ₆ H ₄ (1a) 53 oil (33 ^a ) 2 3-NO ₂ C ₆ H ₄ (1b) 65 46 ~ 47 (47 ^a ) 3 4-NO ₂ C ₆ H ₄ (1c) 70 80 ~ 81 (81 ^a ) 4 2-CNC ₆ H ₄ (1d) 33 41 ~ 43 (43 ^a ) 5 4-CNC ₆ H ₄ (1e) 54 90 ~ 92 (91 ^a ) 6 4-MeOC ₆ H ₄ (1j) 54 87 ~ 89 (89 ^a ) 7 4-NO ₂ -2-MeOC ₆ H ₃ (1k) 65 76-80 8 2-NO ₂ -4-MeOC ₆ H ₃ (1 l) 69 38 ~ 41 (41 ^a )

^a reference mp (Aldrich handbook of fine chemicals)

In addition, ¹ H-NMR analysis of the purely separated products obtained above are shown below. ¹ H NMR spectra were measured in CDCl ₃ using a Bruker 300 MHz spectrometer.

1- chloro -2- nitrobenzene (4a) . Yellow oil, 1 H NMR (300 MHz, CDCl ₃ ) δ 7.86 (d, 1H, J = 8.7 Hz), 7.51 (m, 2H), 7.40 (m, 1H).

1- chloro- 3- nitrobenzene (4b) . Yellow solid, mp: 46-47 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ8.22 (t, 1H, J = 2.1 Hz), 8.12 (d, 1H, J = 8.1 Hz), 7.67 (d, 1H , J = 8.1), 7.42 (t, 1H, J = 8.4 Hz).

1- chloro -4- nitrobenzene (4c) . Yellow solid, mp: 80-81 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ8.16 (d, 2H, J = 8.7 Hz), 7.50 (d, 2H, J = 9.0 Hz).

2- chlorobenzonitrile (4d) . White solid, mp: 41-43 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ7.66 (d, 1H, J = 8.7 Hz), 7.52 (m, 2H), 7.52 (m, 1H).

4- chlorobenzonitrile (4e) . Pale yellow solid, mp: 90-92 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ7.58 (d, 2H, J = 8.7 Hz), 7.49 (d, 2H, J = 8.7 Hz).

1- chloro -2- methoxy -4- nitrobenzene (4k) . White solid, mp: 76-80 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ7.71 (m, 2H), 7.71 (d, 1H, J = 8.4 Hz), 3.99 (s, 3H).

1- chloro -4- methoxy -2- nitrobenzene (4l) . Yellow solid, mp: 38-41 ° C., 1 H NMR (300 MHz, CDCl ₃ ) δ 7.37 (m, 2H), 7.03 (m, 1H), 3.83 (s, 3H).

Through the above results, it was confirmed that the aromatic chloride from the aromatic amine can be easily synthesized in a high yield through the diazotization-chlorination reaction of the present invention.

On the other hand, when comparing the final product of the diazotization-bromination reaction and the final product of the diazotization-chlorination reaction in the present invention, the yield of chloride is lower than bromide, which can be explained by the oxidation potential of the two halogen anions. In other words, the higher oxidation potential of Cl ⁻ makes electron transfer more difficult than Br ⁻ , resulting in low yield. Br ^- it can be a cause of low yields even lower chlorinated nucleophilic Saints ^- than Cl.

In addition, in the present invention, it was confirmed that the Cu salt required for the reaction conditions for obtaining the excellent yield of the desired product was sufficient even in a small amount of the catalytic amount.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (10)

After adding sodium nitrite or alkyl nitrite, p-TsOH, and an ionic halide to the aromatic amine compound of the following formula (I) A method for synthesizing the aromatic bromide or aromatic chloride of (II).
Ar-NH ₂ (I)
Ar-X (II) The method of claim 1,
Ar in formula (I) is phenyl, pyridyl, piperonyl, naphthyl, anthranyl, furyl, indolyl, quinolyl, isoquinolyl, benzooxazolyl, phenanthryl, pyrimidyl, oxazolyl, thiazolyl , Isooxazolyl, isothiazolyl, amidazolyl, pyrazolyl, oxadiazolyl and dinodiazolyl, and optionally substituted aryl and heteroaryl groups selected from the group consisting of
Wherein any substituent is aromatic from an aromatic amine, characterized in that it is selected from the group consisting of halogen, alkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, nitro, amino, alkylamino, carboxy, alkoxycarbonyl and hydroxy Method for synthesizing bromide or aromatic chloride. The method according to claim 1 or 2,
In formula (I), Ar is 4-NO ₂ C ₆ H ₄ , 3-NO ₂ C ₆ H ₄ , 2-NO ₂ C ₆ H ₄ , 4-CNC ₆ H ₄ , 2-CNC ₆ H ₄ , 4 _{-IC 6 H 4, 4-BrC} 6 H 4, 4-ClC 6 H 4, 4-OCH 3 C 6 H 4, 2-OCH 3 C 6 H 4 and _{4-NO 2 -2-OCH 3} C 6 H ₃ , 2-NO ₂ -4-OCH ₃ C ₆ H ₃ A method for synthesizing aromatic bromide or aromatic chlorine from an aromatic amine, characterized in that selected from the group consisting of. The method of claim 1,
Wherein in the formula (II), X is bromine or chlorine. The method of claim 1,
The ionic halide is composed of sodium bromide (NaBr), potassium bromide (KBr), tetrabutyl ammonium bromide (TBAB), and benzyltriethyl ammonium chloride (BTAC). A method for synthesizing an aromatic bromide or aromatic chloride from an aromatic amine selected from the group. The method of claim 1,
Aromatic bromide or aromatic bromide from 0.5 to 2 equivalents of sodium nitrite or alkyl nitrite, 0.5 to 2 equivalents of ionic halide, and 0.5 to 2 equivalents of p-TsOH to 1 equivalent of the aromatic amine compound Method for synthesizing aromatic chlorides. The method of claim 1,
Wherein said small amount of water is used in an amount of 0-1 ml of water per mmol of aromatic amine. The method of claim 1,
The reaction is a method for synthesizing aromatic bromide or aromatic chloride from the aromatic amine, characterized in that carried out for 5 to 60 minutes at 0 ~ 80 ℃. The method of claim 1,
A method of synthesizing an aromatic bromide or aromatic chloride from an aromatic amine further comprising adding a catalytic amount of 0.5 to 5.0 mol% copper (I) salt or copper (II) salt. 10. The method of claim 9,
And wherein said copper (I) salt is CuBr or CuCl, and said copper (II) salt is CuBr ₂ or CuCl ₂ .