JP5907006B2 - Synthesis method of biphenyl compound - Google Patents

Description

  The present invention relates to a method for synthesizing a biphenyl compound using a heterogeneous palladium-supported carbon catalyst and biquinoline by reacting a triphenylbismuth compound with an aromatic iodo compound.

  The cross-coupling reaction between an organic bismuth compound and an aryl halide or aryl halide equivalent in the presence of a palladium catalyst (hereinafter referred to as a Pd catalyst) depends on the stability of the organic bismuth compound in air, Because of the safety of certain inorganic bismuth (inorganic bismuth can also be used in cosmetics, etc.), it has attracted attention as a safe and low environmental impact reaction.

  Many cross couplings using such organic bismuth compounds have been reported so far. In cross coupling using an organic bismuth compound, a method using a palladium catalyst, a ligand, and a base is known, and all of the palladium catalysts used in this method are homogeneous palladium catalysts such as palladium chloride. An example of such a cross-coupling reaction using a conventional homogeneous palladium catalyst is as follows (Non-patent Document 1).

上記式中、ＰｄＣｌ_２は均一系パラジウム触媒である塩化パラジウム水溶液を表し、ＰＰｈ_３はリガンドとして使用されるトリフェニルホスフィンを表し、ＤＭＡは溶剤として使用されるＮ，Ｎ−ジメチルアセトアミドを表し、ＯＴｆはトリフラートアニオンを表し、Ｒ_３はＨ、Ｍｅ又はＭｅＯを表し、Ｒ_４はＡｃ、Ｎ_２Ｏ、ＣＮ、ＣＦ_３、ＣＯＰｈ、ＣＯＯＥｔ、Ｍｅ、Ｃｌ又はＦを表わす。ここでＭｅはメチル、Ｅｔはエチル、Ｐｈはフェニル、Ａｃはアセチルを表す。

In the above formula, PdCl ₂ represents a palladium chloride aqueous solution as a homogeneous palladium catalyst, PPh ₃ represents triphenylphosphine used as a ligand, DMA represents N, N-dimethylacetamide used as a solvent, and OTf Represents a triflate anion, R ₃ represents H, Me or MeO, and R ₄ represents Ac, N ₂ O, CN, CF ₃ , COPh, COOEt, Me, Cl or F. Here, Me represents methyl, Et represents ethyl, Ph represents phenyl, and Ac represents acetyl.

In the above reaction example, 4 equivalents of Cs ₂ CO ₃ as a base is used per 1 equivalent of triphenylbismuth. However, in the cross-coupling reaction using a palladium catalyst, the base is used for the purpose of promoting the metal exchange reaction. Is generally added.

  In the synthesis of a biphenyl compound using a conventional homogeneous Pd catalyst, it was difficult to separate and recover the Pd catalyst from the product. For this reason, there is a concern about residual Pd in the product. Further, in a reaction using a homogeneous Pd catalyst, it is difficult to repeatedly use the Pd catalyst, and it is also difficult to reduce the synthesis cost of the biphenyl compound. On the other hand, in the synthesis of a biphenyl compound using a conventional homogeneous Pd catalyst, a reaction using Pd / C as a heterogeneous catalyst instead of the homogeneous Pd catalyst has not been studied.

  Further, in the cross coupling reaction, as described in Non-Patent Document 1, it is known to use a ligand. The ligand is used for the purpose of improving selectivity, but coordinates as a complex with palladium as a catalyst. Thus, the palladium coordinated with the ligand may be eluted in the solvent, and there is a concern that it remains in the product.

  Furthermore, elution of palladium contained in the catalyst by using a ligand is not preferable when Pd / C, which is a heterogeneous catalyst, is used as the catalyst. The heterogeneous catalyst (Pd / C) is used for the purpose of reusing an expensive catalyst by separating and recovering the Pd catalyst used in the reaction from the product. There is a concern that the concentration of palladium in the used catalyst is lowered, and the desired reaction efficiency cannot be obtained even if it is reused.

Rao, M .; L. N. Jadhav, D .; N. Banerjee, D.M. Tetrahedron 2008, 64, 5762-5572

  The present invention can obtain a biphenyl compound in a high yield without using a ligand such as triphenylphosphine in order to eliminate the above-mentioned drawbacks of the prior art. Biphenyl compound in high yield by cross-coupling reaction using organic bismuth compound and aromatic iodo compound, using heterogeneous Pd / C catalyst that can be separated and recovered The object is to provide a method of obtaining

  The present invention relates to triphenylbismuth represented by the following formula (1):

（式中、Ｒ_１は水素原子、低級アルキル基、又は低級アルコキシ基を示す）と、
下記式（２）で表される芳香族ヨード化合物：

(Wherein R ₁ represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group);
Aromatic iodine compounds represented by the following formula (2):

（式中、Ｒ_２は低級アルキル基、ニトロ基、低級アルコキシ基、アセチル基、又は水素原子を示す。）
とを、溶媒としてＮ−メチル−２−ピロリドン（ＮＭＰ）、触媒として不均一系パラジウム担持炭素触媒、２，２’−ビキノリン及びフッ化セシウムを使用して、不活性ガス雰囲気中で反応させることを特徴とする、下記式（３）で表されるビフェニル化合物：

(In the formula, R ₂ represents a lower alkyl group, a nitro group, a lower alkoxy group, an acetyl group, or a hydrogen atom.)
Are reacted in an inert gas atmosphere using N-methyl-2-pyrrolidone (NMP) as a solvent, a heterogeneous palladium-supported carbon catalyst, 2,2'-biquinoline and cesium fluoride as a catalyst. A biphenyl compound represented by the following formula (3):

（式中、Ｒ_１及びＲ_２は前記の通りである。）
の合成方法を提供する。

(Wherein R ₁ and R ₂ are as described above.)
A synthesis method is provided.

The present invention is described in further detail below.
[Triphenylbismuth]
The triphenylbismuth compound used in the present invention is represented by the formula (1). In Formula (1), R ₁ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms (C1-C3), or an alkoxy group having 1 to 3 carbon atoms (C1-C3), preferably a hydrogen atom or a methyl group. Alternatively, it represents a methoxy group, more preferably a hydrogen atom.

[Aromatic iodine compounds]
In the aromatic iodo compound represented by the formula (2) used in the present invention, R ₂ is a lower alkyl group having 1 to 3 carbon atoms (C1-C3), a nitro group, or 1 to 3 carbon atoms (C1). -C3) a lower alkoxy group, an acetyl group, or a hydrogen atom, preferably a methyl group, a nitro group, a methoxy group, or an acetyl group, particularly a 3- or 4-methyl group, a 4-nitro group, or 4 A biphenyl compound is obtained in high yield when it is an acetyl group.
In the present invention, an aromatic iodo compound is used, but an aromatic bromine compound or an aromatic OTf compound may be used in addition to the aromatic iodo compound, as in the known coupling reaction.
In this application, the aromatic ring of the aromatic iodo compound is a phenyl group, but other polycyclic aromatic hydrocarbons such as heteroaromatic compounds and naphthyl groups, benzopyran and other oxygen-containing heterocyclic compounds were also used. In this case, the method of the present invention can be applied.

  3-9 mol is preferable with respect to 1 mol of triphenylbismuth compounds, and, as for the usage-amount of the aromatic iodo compound in this invention, 5-7 mol is more preferable. The lower limit is a value that satisfies the quantitative proportional relationship for reacting without a shortage, but if it is too much, the yield may be lowered.

[Pd / C catalyst]
The Pd / C catalyst used as the heterogeneous catalyst in the present invention is not particularly limited, but the specific surface area value (BET value), particle size distribution, and Pd amount are preferably in the following ranges.
Specific surface area (BET value); 800~1,500m ² / g, more preferably 1000~1,500m ² / g. If the BET value is too small, the dispersibility of Pd may decrease and the reaction activity may also decrease. If the BET value is too large, the activity of the catalyst itself may increase, but side reactions other than the intended reaction and substrates Decomposition may occur.
Particle size distribution: A particle size distribution (50% particle size distribution) of 50% or more of all particles is preferably included in the range of 10 to 75 μm, and more preferably 45 to 75 μm. If the 50% particle size distribution is too small, it becomes difficult to separate the catalyst after the reaction, and it becomes difficult to reuse the catalyst. If the particle size of the 50% particle size distribution is too large, the surface area of Pd / C per unit volume may be reduced, and the activity of the catalyst may be reduced.
Pd loading amount: 1 to 30 wt% is preferable, 5 to 20 wt% is more preferable, and 7.5 to 12.5 wt% loading is most preferable per unit weight of Pd / C. If the amount of Pd supported is too small, the activity of the catalyst may decrease, and if it is too large, there may be disadvantages in cost, side reactions other than the intended reaction may occur, or decomposition of the substrate may occur. In the step of supporting Pd on the carbon support described later, the Pd metal may be aggregated, and the aggregated Pd metal has a small active surface and the activity as a catalyst may decrease.

The production method of the Pd / C catalyst of the present invention is not particularly limited and may be adjusted by a known method, but an example is shown below.
If necessary, prepare an aqueous solution of a palladium salt whose pH is appropriately adjusted with an acid such as hydrochloric acid or nitric acid, and a carbon support. After mixing these, the palladium salt is reduced with a reducing agent, and the mixture is filtered and washed with water. -It can dry and can obtain Pd / C which carry | supported metallic palladium on the carbon support | carrier.
Here, activated carbon obtained by pulverizing coal, petroleum, coconut shell, wood, or the like can be used as the carbon carrier, but any carbon material having similar properties can be used other than such activated carbon.
As the palladium salt, palladium chloride, palladium nitrate or the like can be used, and as the reducing agent, formalin, methanol, formic acid, hydrazine, sodium borohydride, hydrogen gas or the like can be used. It should be noted that a metal salt other than the palladium salt and other components may coexist as long as the gist of the present invention is not impaired, and a heating step may be added as necessary in the reduction of the palladium salt. .

  The Pd / C catalyst used in the present invention can be produced generally by the method as described above, but a commercially available Pd / C catalyst may be used. Examples of such a Pd / C catalyst include [5% palladium carbon powder K type], [10% palladium carbon powder K type], and [20% palladium carbon powder K type] manufactured by N.E. The percentages of these catalysts are respectively the weight of palladium supported on the metal per unit weight of the catalyst.

  The amount of the Pd / C catalyst used in the present invention is preferably from 1 to 30 mol%, more preferably from 5 to 20 mol% in terms of Pd metal, based on the triphenylbismuth compound of the formula (1). If the amount is too small, the reaction may be slowed or the yield may be reduced. However, if the amount is too large, the cost may be disadvantageous or the reaction promoting effect according to the amount used may not be obtained.

[2,2′-biquinoline]
In the present invention, 2,2′-biquinoline is used as a ligand. The amount of 2,2'-biquinoline is preferably 5 to 50 mol%, more preferably 10 to 30 mol% of the triphenylbismuth compound. The lower limit is a value that satisfies the quantitative proportional relationship for reacting without a shortage, but if it is too large, it may be disadvantageous in terms of cost or the yield may be reduced.

[Cesium fluoride (CsF)]
In the present invention, cesium fluoride (CsF) is used as the base. The amount of CsF is preferably 3 to 9 molar equivalents and more preferably 5 to 7 molar equivalents with respect to the triphenylbismuth compound. If the amount is too small, the reaction may be slowed or the yield may be lowered, but if too much, the yield may be lowered.

[solvent]
In the present invention, N-methyl-2-pyrrolidone (hereinafter referred to as NMP) is used as a solvent. It has been confirmed that by using NMP, the biphenyl compound that is the object of the present invention can be obtained in a particularly high yield. The usage-amount of NMP is 1-20 ml normally with respect to 1 mmol (1 mmol) of a triphenylbismuth compound, Preferably it is 4-15 ml, More preferably, it is 5-10 ml.

  The reaction temperature in the present invention is not particularly limited, but may be room temperature (25 ° C.) or higher, and preferably 70 ° C. or higher for promoting the reaction. In order not to cause decomposition of the product, the temperature is preferably 160 ° C. or lower, more preferably 150 ° C. or lower, and particularly preferably 140 ° C. or lower. The reaction time is usually 12 to 48 hours. As the inert gas in the inert gas atmosphere in which the reaction is performed, nitrogen gas, argon gas, or the like can be used, but argon gas is preferable.

Examples of the present invention will be described below and the present invention will be described more specifically. However, the present invention is not limited to these examples.
[Examples 1-7, Comparative Examples 1-3]
0.25 mmol of the triphenyl bismuth compound, the predetermined amount shown in Table 1 for the aromatic halide compound with respect to the triphenyl bismuth compound, and 10% -Pd / C as a catalyst (trade name of NEM Chemcat Co., Ltd .; 10 % Palladium carbon powder K type (BET value; 1,100 m ² / g, 50% particle size distribution; 45 to 75 μm)) with respect to triphenylbismuth compound in terms of palladium metal, 5 mol%, and 2,2′− as a ligand Biquinoline is 20 mol% with respect to the triphenylbismuth compound, cesium fluoride as the base is 6 equivalents with respect to 1 equivalent of the triphenylbismuth compound, 2 ml of NMP is used as the solvent, and stirred at 140 ° C. in an argon gas atmosphere for 24 hours. Reacted.
Thereafter, the catalyst was filtered and separated, the product obtained by ¹ H-NMR was analyzed, and the yield was measured by GC / MS. The reaction formulas in the examples are shown in the following formula (4), and the results are shown in Table 1.

Then, it verified about the elution amount of Pd with the following reference example.
[Reference Example 1]
In the above Example 1, the following reaction was carried out by the same operation except that the substrate (aromatic halide substituent R2) was changed. Reaction formula (5) is shown below.

（５）

(5)

（６） [Reference Example 2]
Moreover, in order to compare the Pd elution inhibitory effect of this invention, the following reaction was performed by the same operation as the said Example 1 except having changed the substrate, the ligand, the base, and reaction temperature. DABCO, which is a ligand in the formula, is an abbreviation for 1,4-diazabicyclo [2.2.2] octane. Reaction formula (6) is shown below.

(6)

With respect to the above Reference Example 1 and Reference Example 2, the catalyst after the reaction was filtered, and the amount of Pd in terms of metal lost by elution was determined using an inductively coupled plasma emission spectrometer (ICP-AES; Inductively Coupled Plasma-Atomic Emission). Measured by Spectrometry). In [Reference Example 1], it was 2.9 mass%, and in [Reference Example 2], it was 17 mass%. This shows that the elution of the Pd catalyst is remarkably reduced in the reaction using 2,2′-biquinoline as a ligand as in the present invention.

Claims (6)

Triphenylbismuth represented by the following formula (1):

(Wherein R ₁ represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group);
Aromatic iodine compounds represented by the following formula (2):

(In the formula, R ₂ represents a lower alkyl group, a nitro group, a lower alkoxy group, an acetyl group, or a hydrogen atom.)
And N-methyl-2-pyrrolidone (NMP) as a solvent, a heterogeneous palladium-supported carbon catalyst as a catalyst, 2,2′-biquinoline and cesium fluoride in an inert gas atmosphere. A biphenyl compound represented by the following formula (3):

(Wherein R ₁ and R ₂ are as described above.)
Synthesis method. The synthesis method according to claim 1, wherein R ₁ in formula (1) represents a hydrogen atom, a methyl group, or a methoxy group. The synthesis method according to claim 1 or 2, wherein R ₂ in formula (2) represents a methyl group, a nitro group, a methoxy group, or an acetyl group.   The synthesis | combining method of any one of Claims 1-3 whose usage-amount of the said aromatic iodo compound is 3-9 mol with respect to 1 mol of said triphenylbismuth compounds.   The synthesis | combining method of any one of Claims 1-4 whose usage-amount of 2,2'-biquinoline is 5-50 mol% of the said triphenylbismuth compound. The synthesis | combining method of any one of Claims 1-5 whose usage-amount of a cesium fluoride is 3-9 molar equivalent with respect to the said triphenylbismuth compound.