JP2021133312A - Novel porous crosslinked polymer, and immobilizing catalyst and device including the same - Google Patents

Abstract

To provide an immobilizing catalyst, and a synthesis device and a reactor which can be used in continuous flow-type synthetic reaction.SOLUTION: Provided is a crosslinked polymer which has a phosphine ligand, the polymer having a porous structure. Also provided is a porous crosslinked polymer having a constitutional unit (a1, a2, a3) having a phosphine. Also provided are an immobilizing catalyst that contains a porous crosslinked polymer and uses an immobilizing phosphine ligand, and a continuous flow-type organic synthesis device utilizing the same.SELECTED DRAWING: None

Description

The present invention relates to a catalyst using a porous polymer and a continuous flow type synthesizer using the catalyst.

In recent years, continuous distribution type synthesis of precision chemical products has attracted attention. The continuous flow synthesis method is attracting attention as an efficient organic synthesis method due to the stability of temperature control and the stirring effect through the flow process. In the continuous distribution synthesis method, the synthesis can be controlled by distributing the substrate, and the production amount can be easily controlled by the distribution amount. Advantages for batch systems in automation, on-demand production, and safety (eg, Non-Patent Document 1), automation and on-demand production are attracting attention as systems for new chemical production processes based on the development of computer science. (For example, Non-Patent Document 2).

While continuous distribution synthesis methods have attracted attention, they cannot use catalysts that play an important role in the synthesis of refined products in batch systems. Organometallic catalysts mediate many precision organic synthesis reactions, including carbon-carbon bond formation, and are indispensable for synthetic methods of precision chemicals such as chemicals. Therefore, it is desired to develop an immobilization catalyst that can be used even in the continuous flow synthesis method. So far, particle-type immobilization catalysts such as silica gel have been developed for the synthesis of precision products using immobilization catalysts (for example, Non-Patent Document 3). Further, the synthesis of a refined product by flow synthesis in which a particle-type immobilization catalyst is continuously used has been reported (for example, Non-Patent Document 4).
In the continuous flow type synthesis method, it is required that the reaction solvent can be circulated at the same time as having catalytic activity. Particle-type immobilization catalysts are often used because they are easy to prepare and the scale and the like can be freely changed. On the other hand, a column tube filled with particles has a large pressure loss, and it is difficult to circulate a liquid. Further, it has been reported so far that the immobilization of the catalyst tends to be concentrated on the dead end structure portion formed in the form of particles, so that it is difficult to act effectively. It has been reported that a porous material having through holes can be used as an immobilization catalyst for a particle type to allow a substrate solution to flow with a low pressure loss to form a continuous flow type reactor (for example, non-patent literature). 5).

In the immobilized catalyst in the continuous flow synthesis method, it is required to continuously flow the solvent. Since organic synthesis often involves the formation of salts, high porosity and low flow pressure loss are required. Many silica particles and polymer particles have been reported as materials for the immobilization catalyst, but this is not always sufficient because it leads to high pressure loss in the continuous flow reaction, and a material having a higher void ratio is immobilized. It is desirable to use it as a catalyst.

It is known that a porous material using a polymer or silica gel has high flowability, a high flowability of a solution, and a large surface area (for example, Non-Patent Document 6 and Non-Patent Document). 7. Non-patent document 8). It is considered that the porous material can be used in a distribution type synthesizer, and bioreactors using the porous material on which an enzyme is immobilized (for example, Non-Patent Document 9 and Non-Patent Document 10) have been used. Reactors made of a porous material on which Pd is immobilized have been reported (for example, Non-Patent Document 11 and Non-Patent Document 12).

There are various organometallic catalysts, and various organometallic catalysts made of combinations of metals and ligands have been developed and used in the production of refined products. Among them, organophosphorus ligands can be used in many organometallic catalysts and are highly useful. Trialkylphosphine and triphenylphosphine are used in many catalysts because they have high catalytic activity (for example, Non-Patent Document 13). By using a phosphine ligand, high catalytic activity can be exhibited by forming a complex with a metal.

As a phosphine ligand, the usefulness of a phenyl-based phosphine ligand is widely known. As a catalyst for immobilizing triphenylphosphine, a catalyst immobilized on silica particles has been studied by many researchers (for example, Non-Patent Document 14). A material in which a phosphine ligand is bound to a polymer has also been reported (for example, Non-Patent Document 15). As an immobilization catalyst, it is known to be useful for organic chemical reactions using reactions in batches. Continuous flow synthesis using a phosphine ligand immobilized on silica particles and a metal complex has also been reported (for example, Non-Patent Document 16).

So far, Iwai, Sawamura et al. Have produced highly active, polymer-immobilized phosphine ligands that enable cross-coupling reactions of aryl chloride with a copolymer of tris (4-vinylphenyl) phosphine and styrene. We are developing. It has been reported that the catalyst of this immobilization catalyst for this palladium catalyzes the carbon-carbon bond formation cross-coupling of many compounds including aryl chloride (for example, Non-Patent Document 17). In addition, a flow reaction using triphenylphosphine immobilized on polymer particles has also been reported (for example, Non-Patent Document 18).

Polymer compounds can be in a wide variety of material forms depending on the polymerization conditions and molding conditions. So far, a phosphine ligand immobilized on a polymer has been reported, but an immobilized catalyst having a porosity and strength suitable for a continuous flow reaction has not been reported. It is considered necessary to develop a porous immobilized catalyst having a high porosity and catalytic activity suitable for a continuous flow reaction. Some research groups have reported on the porous polymer triphenylphosphine, but not on organic chemical reactions including cross-coupling (for example, Non-Patent Document 19 and Non-Patent Document 20). ..

Jun-ichi Yoshida, The Chemical Record, 2010, 10, 332-341. Jaroslaw M. Granda et al. Nature, 2018, 559, 377-381. Tetsu Tsubogo et al. Angelwante Chem Int. Ed. 2013, 52, 6590-6604. Tetsu Tsubogo et al. Nature, 2015, 520, 329-332. Hikaru Matsumoto et al. ACS omega, 2017, 2, 8796-8802 Porous Silica Gel Material Hiroyashi Minakuchi et al. Analytical Chemistry, 1996, 68, 3498-3501. Polymer Porous Materials Thomas Rohr et al., Macromolecules, 2003, 36, 1677-1684. Keisuke Okada et al. Chemical Communications 2011, 47, 7422-7424. Porous Silica Material Koei Kawakami et al. Int Eng. Chem. Res. 2005, 44, 236-240 Polymer Porous Materials, Jana Krenkova et al. Analytical Chemistry, 2009, 81, 2004-2012. Cross-coupling reaction with porous silica material Grant Chaplain et al. Australian Journal of Chemistry, 2012, 66, 208-212. Cross-coupling reaction with porous polymer materials Roderick C. Jones et al. Tetrahedron, 2009, 65, 7474-7481. Doonald H. Valentine Jr et al. Synthesis, 2003, 3, 0317-0334. Wei Chen et al. Tetrahedron, 2011, 67, 318-325. Lin-Jing Zhao et al. J. Comb Chem 2004, 6, 680-683. Silica particles: Juan de M. Munoz et al. Adv. Synth. Catal. 2012, 35, 3456-3460. Tomohiro Iwai et al. Chemistry A -J, 2014, 20, 1057-1065 Tomohiro Iwai et al. Angewante Chem Int. Ed. 2013, 52, 12322-12326. Tomohiro Ichitsuka et al. ChemCatChem, 2019, 11, 2427-2431 Triphenylphosphine Immobilization Catalysis using a porous polymer Aminocarbonylation Yizhu Lei et al. Transition metal Chemistry, 2016, 41, 1-7 Carbon dioxide conversion reaction using triphenylphosphine-immobilized porous polymer; Zhenzhen Yang et al. ACS Catalyst 2016, 6, 1268-1273

Attempts have been made to immobilize phosphine ligands on macromolecules and silica particles. These immobilized catalysts are prepared as immobilized metal catalysts by coordinating with a metal. However, with these immobilization catalysts, an immobilization catalyst having a high porosity and strength suitable for a continuous flow reaction has not been developed.

Therefore, an object of the present invention is to provide a porous polymer immobilization catalyst which is highly useful for continuous flow reactions. As a method for synthesizing a porous material, a poor solvent is added to a polymerization system and a porous material is obtained by phase separation (polyacrylamide: Shaofeng Xie et al. Journal of Polymer Science, Part A polymer Chemistry, 1997, 35, 1013). -1021) and the heat-induced phase separation method (Yuanrong Xin et al. Polymer, 2012, 53, 2847-2853), but the void ratio was not sufficient.

On the other hand, it has been reported that a polymer having a high porosity can be obtained by mixing an aqueous phase and an organic phase and linking them in an emulsion state (Andrea Barbetta et al., Chemical Communications, 2000, 221). -222. Neil R. Cameron, Polymer 2005, 46, 1439-1449.). Such a method for synthesizing a polymer is called a high internal aqueous phase ratio emulsion and is useful for obtaining a porous polymer, but it is only partially used as an immobilization catalyst. (Palladium-immobilized silica catalyst using in-school aqueous phase ratio emulsion Nicolas Brun et al. New Journal of Chemistry, 2013, 37, 157-168.)

The present invention includes the following aspects.
[1] A crosslinkable polymer in which a random copolymer is crosslinked, wherein the random copolymer contains a phosphine ligand such as a triphenylphosphine ligand (a1), a structural unit (a2) and a crosslinked structural unit (a3). ) And is porous. In particular, the structural unit (a2) relates to a polymer composed of a structural unit composed of styrene, acrylic acid ester, methacrylic acid ester, and acrylamide derivative containing a hydrophobic side chain functional group such as a phenyl group or an alkyl group.
[2] The above-mentioned polymer in which the structural unit is polymerized under mixed conditions of water and an organic solvent and the porosity is 60% or more. That is, it has the above-mentioned structural unit (a1), structural unit (a2) and crosslinked structural unit (a3), is polymerized under emulsion conditions by mixing water and an organic solvent, has a porosity of 60% or more, and has a porosity of 60% or more. It relates to a crosslinked polymer which is porous. The crosslinked polymer of the present invention is in a state of being polymerized under emulsion conditions by mixing water and an organic solvent, has a porosity of 60% or more, and has a porosity property, but is described by a precise physical property value. It is more practical to describe according to the conditions of polymerization.
[3] The above-mentioned polymer in which a metal is coordinated to the structural unit (a1).
[4] An immobilized catalyst in which a metal is coordinated to a polymer having a structural unit (a1) containing the phosphine ligand according to [3].
[5] A continuous flow apparatus comprising a reactor comprising the immobilization catalyst according to [4].
[6] An organic synthesizer comprising a reactor comprising the immobilization catalyst according to [4].

According to the present invention, there is provided a polymer immobilization catalyst having a phosphine ligand applicable to a continuous flow apparatus or an organic synthesis apparatus using water, an organic solvent and a mixed solvent thereof.
Since the polymer of the present invention has a high porosity, an immobilization catalyst having this is useful for a continuous flow reaction or an organic synthesis reaction.
The apparatus including the reactor including the immobilization catalyst of the present invention can be applied to various organic synthesis reactions and is industrially useful.

It is a photograph of a scanning electron microscope of a porous polymer containing a triphenylphosphine structure, and a bar (black) in the figure indicates a length of 10 μm. This is the result of a mercury intrusion test of a porous polymer containing a triphenylphosphine structure. The horizontal axis (X axis) is the pore diameter (unit is m), and the vertical axis (Y axis) is the logarithmic differential pore. volume) (unit is cm ³ / g). ^{It is the result of 31} P-NMR of a porous polymer containing a triphenylphosphine structure, and the horizontal axis (X axis) indicates a chemical shift (unit: ppm). It is the result of the permeation test of THF of a porous polymer containing a triphenylphosphine structure. The horizontal axis (X axis) is Q (unit is mL / h), and the vertical axis (Y axis) is logarithmic volume (logarithmic). differential pore volume) (unit is kPa) is shown. It is a transmission electron microscope image of a porous polymer catalyst on which palladium is immobilized, and the bar (white) in the figure indicates a length of 10 μm. ^{It is the result of 31} P-NMR of a porous polymer catalyst on which palladium is immobilized, and the horizontal axis (X axis) indicates a chemical shift (unit: ppm). It is the result of continuous flow synthesis of cross-coupling using a porous polymer catalyst on which palladium is immobilized, and L represents the length of the tube. In the figure, the horizontal axis (X axis) is τ (unit is h), the vertical axis (Y axis) is u (u in reactor) in the reactor (unit is cm / h), and the lower figure is the yield. (Yield) (unit is%) is shown. It is a transmission type microscope image after the completion of continuous flow synthesis of cross-coupling using a porous polymer catalyst on which palladium is immobilized. The bar (white) in the figure indicates a length of 10 μm, and the black dot indicates palladium. .. This is an example of a continuous flow device or an organic synthesis device including a reactor including the immobilized catalyst of the present invention.

"Constituent unit" means a monomer unit (monomer unit) constituting a polymer.
When "may have a substituent" is described, a hydrogen atom (-H) is replaced with a monovalent group, and a methylene group (-CH _2- ) is replaced with a divalent group. Including both.
"Aromatic hydrocarbon group" means a hydrocarbon group having at least one aromatic ring. The aromatic ring is not particularly limited as long as it is a cyclic conjugated system having 4n + 2 π electrons, and may be a monocyclic type or a polycyclic type. The aromatic ring is an aromatic hydrocarbon ring such as benzene, naphthalene, anthracene, phenanthrene; and a part of carbon atoms constituting the aromatic hydrocarbon ring is replaced with a hetero atom (oxygen atom, sulfur atom, nitrogen atom, etc.). Includes the aromatic heterocycles that have been used.
The "alkyl group" includes linear, branched and cyclic monovalent saturated hydrocarbon groups unless otherwise specified. The same applies to the alkyl group in the alkoxy group.

The “constituent unit composed of a styrene derivative” means a structural unit formed by cleaving a double bond of a styrene derivative, and also includes a structural unit composed of another compound by substituting a hydrogen atom in the aromatic ring of styrene.

The “constituent unit derived from the acrylic acid ester” means a structural unit formed by cleaving the ethylenic double bond of the acrylic acid ester. The "acrylic acid ester" is a compound in which the hydrogen atom at the terminal of the carboxy group of _{acrylic acid (CH 2 = CH-COOH) is replaced with an organic group.}

The “constituent unit derived from the methacrylic acid ester” means a structural unit formed by cleaving the ethylenic double bond of the methacrylic acid ester. The "methacrylic acid ester" is a compound in which the hydrogen atom at the terminal of the carboxy group _{of methacrylic acid (CH 2} = C (CH _{3) -COOH) is replaced with an organic group.}

The “constituent unit derived from an acrylamide derivative” means a structural unit formed by cleaving the ethylenic double bond of the acrylamide derivative. An "acrylamide derivative" is a compound in which one or both hydrogen atoms of the amino group of _{acrylamide (CH 2} = CH-NH _{2) are substituted with an organic group.}

A "continuous flow reactor" is an organic synthesis device using an annular tube for sending a liquid as a reaction device.

The "crosslinkable polymer" is a polymer obtained by using a structural unit having a site to which at least two or more substituents, functional groups and the like can be bonded.

A "random copolymer" is a polymer in which the structural units (a1, a2, and a3) of the present invention are arranged irregularly. Unlike block copolymers, random copolymers do not need to carry out a polymerization reaction for each block, so that production time and production cost can be suppressed.

"Polymerization under emulsion conditions"
The crosslinked polymer of the present embodiment is a system in which water and an organic solvent are mixed, and they are polymerized under the condition of an emulsion in which they are separated into an oil layer and an aqueous layer and then finely dispersed (Andrea Barbetta et al., Chemical Communications, 2000, 221-222). ). Since the constituent unit of the polymer is dissolved in the organic solvent layer and polymerized, the portion where water exists becomes a void, and the polymer has a porosity of 60% or more.

First, the constituent requirements a1, a2, or a3 of the present invention will be described in detail.
(Structural unit (a1))
The constituent requirement a1 of the present invention is a structural formula having an alkyl or arylphosphine skeleton, and a site to which at least one or more substituents, functional groups, etc. can be bonded. It is a structural formula to be used.

（式中、Ｒ^１，Ｒ^２およびＲ^３はそれぞれ同一または異なってよく、置換基を有してもよい炭素数５以上の環状アルキル基、もしくは置換基を有してもよい炭素数６以上のアリール基を表す。ｌおよびｍは、０もしくは１の整数を表す。＊は置換基、官能基等が結合可能な部位を示す。）

(In the formula, R ¹ , R ² and R ³ may be the same or different from each other, and may have a substituent and may have a cyclic alkyl group having 5 or more carbon atoms, or may have a substituent and may have 6 or more carbon atoms. L and m represent an integer of 0 or 1. * Indicates a site to which a substituent, a functional group, etc. can be bonded.)

Specific examples of the alkyl group having 5 or more carbon atoms include a cyclopentyl group, a cyclohexyl group, a cycloheppentyl group, and a cyclooctyl group. Specific examples of aryl groups having 6 or more carbon atoms represent aromatic hydrocarbon rings such as benzene, naphthalene, anthracene, and phenanthrene, and some of the carbon atoms are heteroatoms (oxygen atom, sulfur atom, nitrogen atom, etc.). It may be replaced. The hydrogen atom of the cyclic alkyl group having 5 or more carbon atoms or the aryl group having 6 or more carbon atoms may be replaced with an arbitrary substituent.

Further, the site to which the substituent, functional group, etc. in the general formula a1 can be bonded is not particularly limited, but for bonding with any other structural unit, for example, a raw material in which the site is previously substituted with a vinyl group or the like. Can be used. Specific examples of the raw materials at that time include, for example, the following general formulas a1-1, a1-2 and a1-3.

The structural unit (a1) in the present invention may be one type or two or more types among the above. The ratio of the structural unit (a1) in the present embodiment is preferably 1 mol% or more, particularly preferably 1.5 mol% or more, based on the total (100 mol%) constituting all the polymers.

(Other structural units a2)
The random copolymer has at least one other structural unit in addition to the above-mentioned structural unit (a1), and has at least two structural units. Examples of other constituent units include styrene, alkylated styrene, acrylic acid ester containing an alkyl side chain having 1-10 carbon atoms, methacrylic acid ester, and an acrylamide derivative.

Preferred examples of the structural unit (a2) include the structural units represented by (a2-1), (a2-2), and (a2-3) shown below. Of these, (a2-1) is particularly preferable because it is desirable that it is soluble in an organic solvent and has low solubility in water.

（上記式ａ２−３中、Ｒ１は水素または炭素鎖１から５のアルキル基、Ｒ２は炭素鎖１から１０のアルキル基を示す。）

(In the above formula a2-3, R1 represents hydrogen or an alkyl group of carbon chains 1 to 5, and R2 represents an alkyl group of carbon chains 1 to 10.)

The structural unit (a2) may be one type or two or more types. The ratio of the structural unit (a2) to the polymer in the present embodiment is preferably 20 mol% or more, particularly preferably 30 mol% or more, based on the total (100 mol%) of all the structural units constituting the total random copolymer.

(Other structural units a3)
In addition to (a1) and (a2), the random copolymer has the following (a3-1), (a3-2), as a structural unit for cross-linking a polymer (hereinafter referred to as a cross-linking structural unit (a3)). (A3-3) can be mentioned. Among these, it is desirable that the substance is soluble in an organic solvent and has low solubility in water, and therefore (a3-1) shown below is particularly preferable.

The random copolymer containing the crosslinked polymer contains the structural units of (a1), (a2) and (a3), respectively, and (a1), (a2) and (a3) may contain several structural units.

"Method for producing crosslinkable polymer"
The crosslinkable polymer is polymerized in an emulsion state in which water, an organic solvent and a surfactant are mixed. A polymerizable monomer mixture containing a polymerizable phosphine, a monomer, and a cross-linking agent for inducing each structural unit of the random copolymer can be produced by radical polymerization in the presence of a polymerization initiator.

The crosslinked polymer of the present embodiment is a polymer having a porosity of 60% or more and a large pore size (1 μm-100 μm), and forms a self-supporting structure. Further, it is desirable that the porosity is 74% or more, particularly 74% -99%.
Here, the porosity of the crosslinked polymer can be measured by any known method such as Archimedes method, pycnometer, water absorption rate measurement, and air permeability measurement. The pore size of the crosslinked polymer can be measured by any known method such as a gas adsorption method, a gas permeation method, a gas diffusion method, a mercury intrusion method, and a small-angle X-ray scattering method.

The polymerization initiator may be used those commonly used in the radical copolymerization, potassium peroxodisulfate _{(K 2 S 2 O 8 (} Potassium persulfate)), AIBN (2, 2'-Azobis (isobutyronitrile)), Examples thereof include V-501 (4,4'-Azobis (4-cyanovalic acid)) and AAPD (2,2'-Azobis (2-methyl-propionamide) Dihydrochlide).

As the reaction solvent for radical polymerization, an aqueous medium containing an organic solvent immiscible with water such as chlorobenzene or benzene and a surfactant can be used.

As the surfactant, for example, Span80, sodium dodecyl sulfate (SDS), hexadecyltrimethylammonium bromide (CTAB) and the like can be used.

"Method of preparing metal catalyst"
A metal is added to the phosphine ligand-immobilized polymer to prepare a complex. Examples of the metal to be added include palladium, rhodium, iridium, nickel and the like. In particular, an immobilization catalyst prepared by adding _{PdCl 2} (PhCN) _{2 of palladium is preferable.}

"Continuous distribution type synthesizer"
In one embodiment, the present invention provides an immobilized catalyst made of a porous polymer on which a metal catalyst is immobilized and a continuous flow reactor.

A continuous flow reactor is a device that performs chemical synthesis using a tube that circulates a substrate and a solvent. In the present embodiment, it can be used as an apparatus for performing a chemical reaction using a metal immobilization catalyst using the above-mentioned porous crosslinked polymer. In particular, a metal catalyst on which palladium is immobilized is preferable, but catalysts made of other metals are also possible.

The metal-catalyzed chemical reaction with immobilized phosphine can be applied to many chemical reactions such as Suzuki coupling reaction and Heck reaction. In particular, the carbon-carbon bond formation reaction by Suzuki coupling is suitable. For example, it can be applied to the Suzuki coupling reaction by 1-chloro-4-methylbene and phenylboronic acid.

As the solvent, an organic solvent such as THF or toluene, water, or a mixed solvent thereof can be used. These solvents preferably contain basic salts such as KOH, KF, K ₂ CO ₃ , and K ₃ PO _4.

The product is obtained by injecting a solution of the substrate into a continuous flow reactor and passing it through a layer of a porous solid catalyst. It is desirable that the palladium in the solid catalyst layer does not leak. The amount of substrate injected into the reactor layer determines the amount of product.

In the present embodiment, the porous polymer immobilization catalyst is immobilized in a tube, and a substrate, a basic compound, and a solvent are injected. For example, the substrate 1-methyl-4-chlorotoluene may be circulated in an amount of 100 mol to 3000 mol, that is, 100 to 3000 times as the catalyst rotation speed with respect to 1 mol of palladium.

FIG. 9 shows an example of a continuous flow apparatus or an organic synthesis apparatus including a reactor containing the immobilized catalyst of the present invention.
As shown in FIG. 9, in the continuous flow device or the organic synthesis device 1 according to the embodiment of the present invention, the phosphine ligand, the reaction substrate, the solvent, etc. are sent from the injection syringes 2 and 3, and T. It merges in the character flow path 6. Then, after entering the reactor (column) 4, it comes into contact with the immobilized catalyst layer (inside the column) 5 provided in the reactor 4, and the reaction proceeds.
For example, liquids are sent from the injection syringes 2 and 3 _{to the organic layer side to which, for example, [PdCl 2} (PhCN) ₂ ], a substrate (dissolved in THF, etc.), etc. are sent to _{one of the syringes, and K 3} PO _4. The aqueous layer side to which the liquid (dissolved in water) is sent is merged in the T-shaped flow path 6, and then the liquid is sent to the reactor 4 provided with the immobilized catalyst layer 5 and inside the reactor (column) 4. The organic reaction proceeds in. After that, in FIG. 7, the reaction product is sent out from below the reactor 4. In FIG. 7, the reaction product is fed from below the reactor 4, but the substrate or the like is fed from below the reactor 4, and the reaction product is fed from above the reactor 4. You can also do it.

[Other aspects]
In one embodiment, the present invention provides a catalyst that is applied to a continuous flow reactor that comprises using the porous solid catalyst of the embodiment for cross-coupling.
In one embodiment, the present invention provides a catalyst that applies a porous immobilization catalyst to a continuous flow reactor that uses a metal catalyst with a phosphine ligand.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to the following Examples.
The porosity and pore size of the crosslinked polymer obtained in the following examples were measured by the mercury intrusion method.

Ｍｇ片（99.5％以上、和光純薬社製、2.40g, 100mmol, 4eq）およびマグネチックスターラを300-mL丸底フラスコに入れた。窒素雰囲気下で脱水テトラヒドロフラン（ＴＨＦ）（純度99.5％以上、関東化学社製）（80 mL）を添加したのち、室温および撹拌下で4-Bromostyrene（純度９５％、東京化成社製）（14.64 g, 80 mmol, 3.2eq）を1 hかけ滴下した。 次に、氷-水浴中および撹拌下でＰＣｌ_３（東京化成社製、使用前に蒸留精製したもの）（3.43g, 25mmol, 1eq）を30 minかけ滴下し、さらに室温下で4h反応させた。aq. ＮＨ_４Ｃｌ（純度99.5%以上 東京化成社製）を用いて停止後、混合物をＥｔ_２Ｏ（で抽出した。有機相をMgSO₄で乾燥後、ろ別し、残留溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィ（ＥｔＯＡｃ/ ^ｎｈｅｘａｎｅ ９７：３）で精製し、白色粉末を得た（収量４．８２ｇ, ５７％収率）。 Example 1
<Synthesis of Tris (4-vinylphenyl) phosphine>

Mg pieces (99.5% or more, manufactured by Wako Pure Chemical Industries, Ltd., 2.40 g, 100 mmol, 4eq) and magnetic stirrer were placed in a 300-mL round bottom flask. After adding dehydrated tetrahydrofuran (THF) (purity 99.5% or more, manufactured by Kanto Chemical Co., Inc.) (80 mL) in a nitrogen atmosphere, 4-Bromostyrene (purity 95%, manufactured by Tokyo Kasei Co., Ltd.) (14.64 g) at room temperature and under stirring. , 80 mmol, 3.2 eq) was added dropwise over 1 h. _{Next, PCl 3} (manufactured by Tokyo Kasei Co., Ltd., distilled and purified before use) (3.43 g, 25 mmol, 1eq) was added dropwise over 30 min in an ice-water bath and under stirring, and further reacted at room temperature for 4 hours. .. aq. _{After stopping with NH 4} Cl (purity 99.5% or more manufactured by Tokyo Kasei Co., Ltd.), the mixture _{was extracted with Et 2} O (. The organic phase was dried with DDL ₄ , filtered off, and the residual solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / ⁿ hexane 97: 3) to give a white powder (yield 4.82 g, 57% yield).

This was analyzed and the following results were obtained.
^{1 1} H NMR (CDCl ₃ ): δ 5.27 (d, J = 11.0 Hz, 3H), 5.77 (d, J = 17.4 Hz, 3H), 6.70 (dd, J = 17.4, 11.0 Hz, 3H), 7.23-7.38 (m, 12H).
¹³ C NMR (CDCl ₃ ): δ 114.85 (3C), 126.44 (d, J _CP = 7.1 HZ, 6C), 134.00 (d, J _CP = 19.2 Hz, 6C), 136.45 (3C), 136.72 (d, J) _CP = 10.1 Hz, 3C), 138.07 (3C).
³¹ P NMR (CDCl ₃ ): δ-6.21.

Example 2
<Polymerization under emulsion conditions>
Tris (p-vinylphenyl) phosphine (1 equivalent) (above and Iwai et al., Angelwante Chem Int. Ed. 2013, 52, 12322-12326), divinylbenzene (purity 80% or more, 20 equivalents manufactured by Sigma Aldrich), And 4-tertbutylstyrene (purity 90% or more, manufactured by Tokyo Kasei Co., Ltd., 41 equivalents) was polymerized to prepare a porous polymer. Monomers (Tris (4-vinylphenyl) phosphorine, divinylbenzene, and 4-tertbutylstyrene) (in total) in glass vials (approximately 20 mm id) containing a stirrer (20 mm x 4 mm, rod-shaped). 1.0 mmol), chlorobenzene (purity 99% or more, manufactured by Wako Pure Chemical Industries, Ltd., 0.19 mL), and Span 80 (manufactured by Tokyo Kasei Co., Ltd., 0.06 mL) were mixed to obtain a uniform organic phase. The organic phase was degassed by three freeze-thaw cycles. Separately, potassium peroxodisulfate (purity 99% or more, manufactured by Wako Pure Chemical Industries, Ltd., 1.9 mol%) is dissolved in an aqueous solution of calcium chloride (purity 95% or more, manufactured by Wako Pure Chemical Industries, Ltd.) (0.10 mol L ^-1). Got Nitrogen was supplied to the solution to degas the aqueous phase. Here, the volume ratio of the organic solvent and the water solvent was set to 1: 9 v / v. Using a syringe, the aqueous phase was added dropwise to the organic phase under stirring (500 rpm). After all the additions were made, the mixture was further stirred for 5 minutes to obtain an emulsion in which the solution was suspended in white. The resulting emulsion was incubated at 70 ° C for 6 hours. The obtained porous polymer was mixed with tetrahydrofuran (THF) (manufactured by Wako Pure Chemical Industries, Ltd. containing a 99.5% pure stabilizer), water (water is MilliQ water) in a 1: 1 mixed solvent (1: 1 v / v) and THF. Each was immersed and washed. After washing, it was vacuum dried overnight at room temperature to obtain a white solid (yield 142 mg, yield 92%).

Example 3
<Evaluation of porous polymer>
The porous polymer was analyzed by a scanning electron microscope (SU8000, manufactured by Hitachi, Ltd.) and a mercury press-fitting method (autopore, manufactured by Shimadzu Corporation). As shown in FIGS. 1 and 2, it was revealed that the polymer was a porous polymer having a pore size of 1-100 μm.
As shown in FIG. 3, it was confirmed that the target compound was obtained by analysis by ^{31 P-NMR.}
As shown in FIG. 4, a permeation test of THF was carried out, and it was confirmed that it had a porous structure in which THF could permeate and had a high transmittance.

Example 4
<Preparation of palladium coordination catalyst>
The dried porous polymer (200 mg, 0.02 mmol) was placed in a glass vial, and [PdCl ₂ (PhCN) ₂ ] (Bis (benzonitrile) palladium (II) Dichloride, manufactured by Tokyo Kasei Co., Ltd.) (3.8 mg, 0.01). A THF solution (10 mL) of mmol, P / Pd 2: 1) was added. It was sealed and immersed for 2 h at room temperature. The mixture was filtered using a cotton wool stopper, washed with THF, and the residual solvent was removed under vacuum to obtain a yellow solid.

The obtained solid was measured with a transmission electron microscope (FEI TECNAI-20, manufactured by Thermo Corporation), and immobilization of palladium was observed as black spots of 2 nm or less (Fig. 5).
In addition, under a resonance frequency of 203 MHz, analysis was performed by ³¹ P cross-polarization / magic angle spinning nuclear magnetic resonance spectroscopy (CP / MAS NMR) using a Bruker AVANCE III 500 spectrometer (manufactured by Bruker), and it was based on the coordination of palladium. The change in the peak of P was observed (Fig. 6).

その結果、有機層／水層からなる二相系反応において、ＰＳ−ＴＰＰ−Ｐｄにより反応は進行した。反応は反応時間２時間の間では、撹拌速度に概ね比例して進行し、収率も撹拌速度が大きく寄与することが分かった。しかしながら、カラム系における反応ではどのような要因で反応速度が制御されるか不明であり、以下の実施例により確認した。 <Continuous distribution synthesis of cross-coupling using a palladium-immobilized catalyst>
In performing continuous flow synthesis of cross-coupling using a palladium-immobilized catalyst, as a reference example, the following cross-coupling reaction was carried out by a batch reaction system in a liquid-liquid two-phase system.

As a result, in the two-phase reaction consisting of the organic layer / aqueous layer, the reaction proceeded by PS-TPP-Pd. It was found that the reaction proceeded substantially in proportion to the stirring speed during the reaction time of 2 hours, and the stirring speed also greatly contributed to the yield. However, it is unclear by what factor the reaction rate is controlled in the reaction in the column system, and it was confirmed by the following examples.

Example 5
The porous polymer was polymerized in a stainless steel column and subsequently supported on palladium, and washed with THF (2.5 hours, residence time = 0.5 hours). 4-Chlorotoluene (purity 98% or higher, Tokyo Chemical Industry, 0.5 mol / L, 1eq.), Phenylboronic acid (purity 97% or higher, Tokyo Chemical Industry, 0.75 mol / L, 1.5eq.), And tetrabutylammonium A THF (purity 99.5% or higher, manufactured by Wako Pure Chemical Industries, Ltd.) solution of bromide (purity 98% or higher, Tokyo Chemical Industry, TBAB, 0.05 mol%) was prepared and filled in a gas tight syringe. Separately, _{an aqueous solution of K 3} PO ₄ (purity 97% or more, manufactured by Wako Pure Chemical Industries, Ltd., 3 mol / L, 3eq.) Was prepared and filled in a gas tight syringe. The two-phase reaction solution was simultaneously supplied using two syringe pumps via a T-channel (THF phase / aqueous phase, 2: 1 v / v). The THF phase and aqueous phase flowing out of the column were continuously collected. DG-980-50 Degassa, PU-980 Pump (manufactured by JASCO Corporation), Mightysil RP-18 GP 250-4.6 column (manufactured by Kanto Chemical Co., Ltd.), UV-2077Plus UV Detector (manufactured by JASCO Corporation), and The yield in the THF phase was calculated by high performance liquid chromatography using an LC-2000Plus system (manufactured by JASCO Corporation) equipped with a CO-2065 Plus column oven (manufactured by JASCO Corporation). The yield of the product (4-methyl-1,1'-biphenyl) at that time is shown in FIG. 7 below.
After the reaction, the column was washed by supplying THF / water (2: 1 v / v) and then THF (2.5 hours, residence time = 0.5 hours). The porous polymer in the column was dried under vacuum.

In FIG. 7, the residence time τ shown on the horizontal axis (X axis) is obtained by τ = column length (cm) / linear velocity (linear velocity (u) (cm / h)). The linear velocity u (linear velocity) shown on the vertical axis (Y axis) in the upper part of FIG. 7 is obtained by u = column length (cm) / residence time (h).
From FIG. 7, the smaller the linear velocity u shown in the upper figure, the higher the yield, and in FIG. 7, the yield becomes maximum at τ = 1.5h. An increase in τ results in an increase in catalyst-substrate contact and a decrease in linear velocity u (relaxation of agitation). Therefore, it can be inferred that by increasing the column length, u can be held larger and the reaction efficiency can be improved.

Example 6
<Investigation of Palladium Leakage>
Inductively coupled plasma-atomic absorption spectrometry was used to quantify palladium spillage during palladium support, catalytic reactions, and post-reaction washing. The effluent from the column (THF or aqueous phase) was diluted 10-fold with HCl (1 mol / L), and the palladium concentration was measured using a Seiko Instruments SPS-1700 HVR spectrometer (manufactured by Seiko Instruments Inc.). In addition, the state of palladium on the column after use was observed with a transmission electron microscope (FIG. 8).
Inductively coupled plasma-atomic absorption spectrometry revealed that palladium was below the detection limit and there was no leakage. As shown in FIG. 8 with a transmission electron microscope, palladium particles were observed.

1 Continuous flow device or organic synthesizer 2, 3 Syringe for injection 4 Reactor (column)
5 Immobilization catalyst layer (inside the column)
6 T-shaped flow path

Claims (7)

A crosslinkable polymer in which a random copolymer is crosslinked, wherein the random copolymer has a structural unit (a1), a structural unit (a2) and a crosslinked structural unit (a3) containing a phosphine ligand, and is porous. polymer. The polymer according to claim 1, wherein the phosphine ligand is a triphenylphosphine ligand. The polymer according to claim 1 or 2, wherein the structural unit is polymerized under mixed conditions of water and an organic solvent, and the porosity is 60% or more. The polymer according to any one of claims 1 to 3, wherein a metal is coordinated to the structural unit (a1). An immobilized catalyst containing the polymer according to any one of claims 1 to 4. A continuous flow apparatus comprising a reactor comprising the immobilized catalyst according to claim 5. An organic synthesizer comprising a reactor comprising the immobilized catalyst according to claim 5.

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