JP2007084470A - Catalytic-carbonylation in micro flow system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To realize a catalytic-carbonylation reaction using a transition metal catalyst in a continuous and safety micro flow system. <P>SOLUTION: The invention relates to the method for producing the carbonyl compounds by reacting a substrate represented by the formula: R<SP>1</SP>-X [R<SP>1</SP>is a monovalent organic group, X is a group which can be eliminated from the R<SP>1</SP>] with carbon monoxide in the presence of a solvent and the transition metal catalyst in the micro flow system. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a carbonyl compound by a carbonylation reaction using an organic compound having a leaving group and carbon monoxide in a microflow system.

  The carbonylation reaction is a basic and important reaction that enables carbon monoxide to be introduced into an organic compound as a carbonyl group. The reaction of carbonylating an organic compound having a leaving group with carbon monoxide to obtain the corresponding carbonyl compound is particularly useful in the fields of pharmaceuticals, agricultural chemicals and electronic materials.

For example, Non-Patent Document 1 discloses a carbonylation reaction using carbon monoxide of the following reaction formula in a batch system.

When batchwise carbonylation using a transition metal catalyst is performed, (1) the problem that it is difficult to produce the product continuously, (2) when carbon monoxide is charged into and extracted from the reaction vessel. There is a problem that the danger of sucking is very high, and (3) a problem that productivity is low.
Schoenberg, A .; Bartoletti, I .; Heck, RFJ Org. Chem. 1974, 39, 3318.

An object of the present invention is to realize a carbonylation reaction using a transition metal catalyst in a microflow system capable of continuous and safe reaction.
That is, it is to provide a carbonylation reaction of an organic compound using a transition metal catalyst and carbon monoxide, which solves the above problems.

Said subject is solved by the invention shown below.
That is, the present invention is a microflow method in the presence of a solvent and a transition metal catalyst.
R ¹ -X
[Wherein, R ¹ is a monovalent organic group, and X is a group capable of leaving R ¹ . ]
To a method for producing a carbonyl compound by reacting carbon monoxide with a substrate represented by the formula:

According to the present invention, a carbonyl compound can be produced from an organic compound and carbon monoxide in a very short time and at a high speed.
The production method of the present invention can be carried out in a particularly simple and reproducible manner, and has high safety to humans and the environment.

  In the present invention, carbonylation is performed in a microflow system. In the present invention, a flow type microreactor having a microchannel diameter (that is, an inner diameter of the microreactor) in the order of millimeters (particularly, 5 mm or less) is used. It is preferable to use a micromixer with the microreactor. There are flow paths inside the microreactor and micromixer. The cross-sectional shape of the channel is generally circular. The upper limit of the diameter (inner diameter) of the microchannel of the microreactor may be 3 mm, for example 2 mm, in particular 1 mm. The lower limit of the diameter of the microchannel of the microreactor is not particularly limited, but may be, for example, 0.005 mm, particularly 0.01 mm, particularly 0.05 mm, or even 0.1 mm. The numbers for the upper and lower limits of the diameter of the micromixer channel are the same as the numbers for the upper and lower limits of the diameter of the microreactor. The diameter of the flow path of the micromixer in which the reactants are mixed may be the same as or different from the diameter of the flow path of the microreactor.

The organic compound R ¹ -X is used as a substrate (first substrate). The first substrate has the formula:
R ¹ -X
[Wherein, R ¹ is a hydrocarbon group having 1 to 30 carbon atoms which may have a sulfur atom, an oxygen atom and / or a nitrogen atom, and X is a leaving group (particularly a halogen atom). ]
It is a leaving group containing organic compound shown by these. In the first substrate, the leaving group (X) is released from R ¹ . The first substrate is preferably an organic halogen compound having a carbon-halogen bond.

The R ¹ group may be a saturated or unsaturated linear, branched or cyclic aliphatic hydrocarbon, or an aromatic hydrocarbon. The carbon number of the R ¹ group may be 1 to 30, for example 3 to 25, in particular 5 to 18, especially 6 to 15. The R ¹ group may be substituted or unsubstituted. A preferred example of the R ¹ group is an unsubstituted or substituted phenyl group.
Specific examples of the R ¹ group include a methyl group, an ethyl group, a propyl group (for example, isopropyl group), a butyl group (for example, t-butyl group), a hexyl group, an octyl group, a nonyl group, and a dodecyl group (for example, n- Chain alkyl groups such as dodecyl groups);
A cyclic alkyl group such as cyclopropyl group, cyclobutyl group, cyclohexyl group;
An aryl group such as a phenyl group;
An arylalkyl group such as a benzyl group;
Alkenyl groups such as ethenyl, propenyl, and allyl;
An alkynyl group such as an ethynyl group;
It is a heterocyclic group such as a thiophene group, a pyrrole group, a furan group, a pyridine group or a thiazole group (particularly an unsaturated ring heterocyclic group).

Examples of the X group are a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom) or a triflate (—OSO ₂ CF ₃ ).
Specific examples of the first substrate include benzyl chloride, allyl chloride, isobropyl chloride, t-butyl chloride, n-hexyl chloride, n-dodecyl chloride, phenyl chloride, vinyl chloride, thiophene chloride, n-dodecyl bromide, phenyl bromide. , Benzyl bromide, allyl bromide, CH ₃ -C ₆ H ₄ -Br, CH ₃ OC ₆ H ₄ -Br, FC ₆ H ₄ -Br, methyl iodide, benzyl iodide, allyl iodide, n-iodide - dodecyl, and the like _{CH 3 -C 6 H 4 -I,} C 6 H 5 -I, CH 3 OC 6 H 4 -I, FC 6 H 4 -I.

  Carbon monoxide is generally gaseous. The pressure of the carbon monoxide gas may be 0.1 to 20 MPa, for example 0.2 to 10 MPa, in particular 0.3 to 5 MPa, especially 0.5 to 3 MPa. The amount of carbon monoxide may be 1 to 200 mol, for example 2 to 100, in particular 3 to 50, with respect to 1 mol of the first substrate. The carbon monoxide flow rate is adjusted to the molar ratio of carbon monoxide / organohalogen compound described above.

The transition metal catalyst is preferably an organometallic compound containing a transition metal. Examples of the transition metal exhibiting catalytic activity include palladium, platinum, rhodium, nickel, ruthenium, iron, cobalt, iridium and the like. The transition metal catalyst is preferably a complex. Carbene complexes are particularly preferred.
Examples of transition metal catalysts are as follows.
MCl ₂ (PPh ₃ ) ₂ , M (OAc) ₂ , MCl ₂ , M (PPh ₃ ) ₄ , M (CO) n, MCln (PPh ₃ ) m
[M is a transition metal. ]
The amount of the transition metal catalyst may be 0.0001 to 0.5 mol, for example, 0.01 to 0.05 mol with respect to 1 mol of the first substrate.

In the present invention, in addition to the first substrate (R ¹ -X), the formula: R ² -Y
[Wherein R ² is a monovalent organic group, and Y is a group capable of leaving R ² . ]
It is also preferable to use a second substrate represented by The reaction formula for the first substrate, carbon monoxide and the second substrate is as follows.
^{R 1 -X + CO + R 2} -Y → R 1 -C (= O) -R 2 + Y-X

In the second substrate, examples of Y are a hydrogen atom, —Sn (C ₄ H ₉ ) ₃ group, and —B (OH) ₂ group.
In the second substrate, examples of ^{R 2 groups, R 21} - group, or ^R 21 -O- or ^(R 21) is -N-. R ²¹ may be a saturated or unsaturated linear, branched or cyclic aliphatic hydrocarbon, or an aromatic hydrocarbon. The carbon number of the R ²¹ group may be 1-30, such as 3-25, especially 5-18, especially 6-15. The R ²¹ group may be substituted or unsubstituted.
Specific examples of the R ²¹ group include a methyl group, an ethyl group, a propyl group (for example, isopropyl group), a butyl group (for example, t-butyl group), a hexyl group, an octyl group, a nonyl group, and a dodecyl group (for example, n- Chain alkyl groups such as dodecyl groups);
A cyclic alkyl group such as cyclopropyl group, cyclobutyl group, cyclohexyl group;
An aryl group such as a phenyl group;
An alkenyl group such as an ethenyl group or a propenyl group;
An alkynyl group such as an ethynyl group;
It is a heterocyclic group such as a thiophene group, a pyrrole group, a furan group, a pyridine group or a thiazole group (particularly an unsaturated ring heterocyclic group).

The second substrate containing a hydrogen atom may be R ²¹ —H, R ²¹ —OH, (R ²¹ ) ₂ —NH, (R ²¹ ) —NH ₂ . Examples of the second substrate containing no hydrogen atom are R ²¹ —Sn (C ₄ H ₉ ) ₃ and R ²¹ —B (OH) ₂ .
Specific examples of the second substrate are phenylacetylene, methyl alcohol, ethyl alcohol, propanol, butanol, benzyl alcohol, diethylamine, dipropylamine, butylamine, benzylamine, phenyltributyltin, vinyltributyltin, phenylboric acid, and vinylboric acid.
The amount of the second substrate may be 1.0-5.0 mol, for example 1.1-2.0 mol, in particular 1.2-1.5 mol, relative to 1 mol of the first substrate.

  Reactions between the first substrate, carbon monoxide, and the second substrate produce ketones, esters, amides, ketoamides, and the like.

In the present invention, a solvent is used. The solvent is preferably inert to the carbonylation reaction. Examples of solvents are organic solvents and ionic liquids. It is preferable that the solvent is an ionic liquid.
Examples of organic solvents are aliphatic hydrocarbons (eg octane and cyclohexane), aromatic hydrocarbons (eg toluene), ketones (eg acetone and methyl ethyl ketone), ethers (eg diethyl ether, tetrahydrofuran), nitriles (eg acetonitrile) ), Esters (eg ethyl acetate), sulfoxides (eg dimethyl sulfoxide), amides (eg N, N-dimethylformamide) and the like.
An ionic liquid is a salt that exhibits a liquid phase at room temperature (20 ° C.). Examples of the ionic liquid include imidazole, ammonium, pyridinium, and phosphonium. Specific examples of the imidazole-based ionic liquid are as follows.

[上記式中、Ｂｕはブチル基、Ｅｔはエチル基、Ｔｆはトリフルオロメタンスルホニル基である。]
溶媒は、第１基質、第２基質および遷移金属触媒を溶解することが好ましい。溶媒の量は、第一基質１モルに対して０．１〜２０ｍＬ、例えば０．２〜１０ｍＬ、特に０．５〜５ｍＬであってよい。
本発明によれば、触媒を溶解したイオン液体をリサイクルできる。

[In the above formula, Bu is a butyl group, Et is an ethyl group, and Tf is a trifluoromethanesulfonyl group. ]
The solvent preferably dissolves the first substrate, the second substrate, and the transition metal catalyst. The amount of solvent may be 0.1-20 mL, for example 0.2-10 mL, in particular 0.5-5 mL, relative to 1 mol of the first substrate.
According to the present invention, an ionic liquid in which a catalyst is dissolved can be recycled.

In the present invention, a base may be present in addition to the solvent. The base serves to capture YX generated in the carbonylation reaction.
Specific examples of the base are nitrogen compounds such as triethylamine and tripropylamine, sodium carbonate, potassium carbonate, sodium hydroxide, calcium hydroxide and potassium hydroxide.
The amount of base may be 1 to 10 mol, for example 1.1 to 5 mol, in particular 1.2 to 3 mol, relative to 1 mol of the first substrate.

  In the present invention, the reaction temperature may be, for example, 30 to 150 ° C, particularly 50 to 100 ° C. The reaction time (residence time) may be, for example, 0.1 to 200 minutes, in particular 0.2 to 100 minutes, in particular 0.5 to 50 minutes.

In the present invention, a microreactor having a microchannel is used.
In the microreactor, a reaction solution containing a substrate and a transition metal catalyst is reacted with carbon monoxide gas.
Carbon monoxide is supplied to the micromixer by controlling the flow rate using a mass flow controller.
The reaction solution is supplied using a pump capable of high-pressure liquid feeding, such as a plunger pump.
A back pressure valve is provided at the outlet of the microreactor having the microchannel, and the inside of the microchannel is controlled to a predetermined pressure.
In the method of the present invention, a liquid or molten organic compound and gaseous carbon monoxide are reacted in a microreactor for a residence time, and the carbonylated organic compound is simply removed from the reaction mixture as desired. Release.

The apparatus used for carbonylation is shown in FIG. 1 includes a substrate container 11, an HPLC pump 12, a catalyst solution container 21, a check valve 22, a carbon monoxide cylinder 31, a mass flow controller 32, a pressure monitor 33, a check valve 34, a first T-shaped mixer 41, and the like. It has a second T-shaped mixer 42, a microchannel reactor 43, a pressure control valve 44, and a product container 45.
The diameter of the flow path in FIG. 1 is 1000 micrometers. Carbon monoxide is introduced from the cylinder 31 while controlling the flow rate using the mass flow controller 32. The substrate mixture is fed using a syringe pump capable of feeding even under high pressure, mixed with carbon monoxide using a T-shaped mixer, and then reacted in a wire-type residence time unit. The system pressure is regulated by a back pressure valve connected after the residence time unit. A sectional view of the T-shaped mixer is shown in FIG.
In the apparatus of FIG. 1, a T-shaped mixer (T-shaped micromixer) is used, and a slag flow (gas phase and liquid phase alternately) of gas (carbon monoxide gas) and liquid (ionic liquid or organic solvent). Side-by-side flow) is formed, and the contact area between the gas phase and the liquid phase is increased.
The gas-phase flow and the liquid-phase flow that flow into the first T-shaped mixer form an angle of 180 °, and two kinds of fluids that flow into the second T-shaped mixer (that is, the gas-liquid phase and the liquid phase (substrate)) ) Forms an angle of 90 °. The angle is not limited to 180 ° or 90 °. In the first T-shaped mixer and the second T-shaped mixer, the angle formed by the two inflowing fluids is 0 ° to 180 ° (particularly 30 ° to 180 °). Good.

  The present invention will be specifically described below with reference to examples and comparative examples.

Comparative Example 1
A ternary linking reaction of aromatic iodide, terminal acetylene and carbon monoxide with a Pd catalyst in an ionic liquid was performed in a batch system using a stainless steel pressure reactor.

Example 1
The reaction of Comparative Example 1 was performed in a microflow system. An apparatus as shown in FIG. 1 was used.
PdCl ₂ (PPh _{3) 2} as a catalyst is difficult to use in a micro flow system for insoluble in the ionic liquid. Since this complex reacts with ionic liquid to give Pd carbene complex A in the system, Pd carbene complex A soluble in the ionic liquid was used to perform the reaction in a microflow system. As a result, a coupling product was obtained with a good yield.

イオン液体[bmim]PF₆にPdカルベン錯体を溶解し、内径1000 マイクロメートルのT字型マイクロミキサーで一酸化炭素（20 atm）と混合した。続いて内径400 マイクロメートルのT路型マイクロミキサーで2−ヨードトルエン、フェニルアセチレン、トリエチルアミンの混合物と混合し、内径1000 マイクロメートルのチューブ型リアクター（1８m）で１２０℃、滞留時間３４分でフロー系で反応を行なったところアセチレンケトンが収率81％で得られた。一酸化炭素５気圧では、収率は９２％であった。
この反応を一酸化炭素圧5気圧で行なってもカルボニル化生成物が良好に得られた。
一方、一酸化炭素圧５気圧でPdCl₂(PPh₃)₂を触媒として用いたバッチ反応（比較例２）では、薗頭カップリング生成物が２３％副成し、カルボニル化生成物の収率は５２％にとどまった（表１、 entry 1）。 Example 2 and Comparative Example 2
An experiment of catalytic carbonylation reaction in a microflow system using a Pd carbene complex as a catalyst was carried out (Example 2).
The reaction was performed under the following conditions.

The Pd carbene complex was dissolved in the ionic liquid [bmim] PF ₆ and mixed with carbon monoxide (20 atm) with a T-shaped micromixer having an inner diameter of 1000 micrometers. Subsequently, it was mixed with a mixture of 2-iodotoluene, phenylacetylene and triethylamine in a T-path type micromixer with an inner diameter of 400 micrometers, and a flow system at a temperature of 120 ° C. and a residence time of 34 minutes in a tubular reactor (18 m) with an inner diameter of 1000 micrometers. The reaction was carried out at a yield of 81% acetylene ketone. At 5 atm of carbon monoxide, the yield was 92%.
Even when this reaction was carried out at a carbon monoxide pressure of 5 atm, a carbonylation product was successfully obtained.
On the other hand, in the batch reaction using PdCl ₂ (PPh ₃ ) ₂ as a catalyst at a carbon monoxide pressure of 5 atm (Comparative Example 2), the Sonogashira coupling product was by-produced by 23%, and the yield of the carbonylation product was Only 52% (Table 1, entry 1).

Examples 3-5 and Comparative Examples 3-5
Other substrates were examined. In the microflow reaction (entry 2: Example 3, entry 3: Example 4, entry 4: Example 5), no production of Sonogashira coupling product was observed. In each case of batch reaction (entry 2: comparative example 3, entry 3: comparative example 4, entry 4: comparative example 5), about 20% Sonogashira coupling product was produced.
The superiority in the microflow system is thought to be due to the high-efficiency mixing in the micromixer and the high gas-liquid interface area associated with the realization of the slag flow in which the gas-liquid alternates.

^a Reaction conditions; microflow system: 1 (7 mmol), 2 (8.4 mmol), Et₃N (25.2 mmol), CO (10 atm), Pd-catalyst A (1 mol%), [bmim]PF₆ (17mL); flow rate: mixture of 1, 2, and Et₃N (0.04 mL/min), CO (0.5 mL/min), A/[bmim]PF₆ (0.14 mL/min); 120 ℃, residence time: 12 min; batch system: 1 (1 mmol), 2 (1.2 mmol), Et₃N (3.6 mmol), CO (5 atm), PdCl₂(PPh₃)₂ (1 mol%), [bmim]PF₆ (3 mL), 120 ℃, 1 h. ^b Yields were determined by ¹H NMR using p-methoxyanisole as an internal standard. ^c The reaction was carried out under 10 atm of CO. For the microflow system, flow rate: 0.5 mL/min.

^a Reaction conditions; microflow system: 1 (7 mmol), 2 (8.4 mmol), Et ₃ N (25.2 mmol), CO (10 atm), Pd-catalyst A (1 mol%), [bmim] PF ₆ (17 mL ); flow rate: mixture of 1, 2, and Et ₃ N (0.04 mL / min), CO (0.5 mL / min), A / [bmim] PF ₆ (0.14 mL / min); 120 ℃, residence time: 12 min; batch system: 1 (1 mmol), 2 (1.2 mmol), Et ₃ N (3.6 mmol), CO (5 atm), PdCl ₂ (PPh ₃ ) ₂ (1 mol%), [bmim] PF ₆ ... (3 mL), 120 ℃, 1 h b Yields were determined by 1 H NMR using p-methoxyanisole as an internal standard c The reaction was carried out under 10 atm of CO For the microflow system, flow rate: 0.5 mL / min.

In Table 1, it was used PdCl ₂ (PPh _{3) 2} in the reaction in a batch system.

Comparative Example 6
The complex PdCl ₂ (PPh ₃ ) ₂ is converted to a Pd carbene complex in the system, but the difference between the microflow system and the batch system may have been caused by the difference in the catalyst species. The reaction was carried out in a batch system. As a result, 36% of the carbonylation product and 37% of the Sonogashira coupling product were produced at a ratio of approximately 1: 1. From this, it is difficult to consider the selectivity due to the catalyst species, and it is thought that the selectivity is also improved by highly efficient mixing in the microflow system.

Example 6
We examined how much the carbon monoxide pressure could be lowered. As a result, when iodobenzene was used, only the carbonylation product was obtained in a yield of 59% even at a carbon monoxide pressure of 3 atm. Even when iodoanisole was used, only the carbonylation reaction proceeded satisfactorily at a carbon monoxide pressure of 3 atm. However, when the carbon monoxide pressure was set at 2 atm, a Sonogashira coupling product was formed as a by-product (carbonylation). 64% product, 9% Sonogashira coupling product). When p-fluoroiodobenzene was used, a Sonogashira coupling product was by-produced at a carbon monoxide pressure of 3 atm.

Example 7 and Comparative Example 7
In the microflow system, carbonylation proceeded well even with low-pressure carbon monoxide. Whether or not this phenomenon is generally observed when using other ionic liquids or organic solvents, was investigated in a microflow system (Example 7) using low-viscosity ionic liquid [bmim] NTf ₂ and DMF. It was. In the reaction in the batch system (Comparative Example 7) using [bmim] NTf ₂ , the Sonogashira coupling reaction proceeds rapidly, so that the Sonogashira coupling product is produced even at a carbon monoxide pressure of 20 atm. It was. When this reaction was carried out in a microflow system, no Sonogashira coupling product was observed, and a carbonylation product was selectively obtained.

Example 8 and Comparative Example 8
When DMF was used and examined in a microflow system (Example 8) and a batch system (Comparative Example 8) at a carbon monoxide pressure of 5 atm, only a carbonylation product was produced in either case.

  Other catalytic carbonylation reactions were investigated in a microflow system.

Example 9 and Comparative Example 9
The esterification reaction (Heck carbonylation) was performed in a microflow system (Example 9) and a batch system (Comparative Example 9). The reaction conditions and results are shown below. In the microflow system, the reaction proceeded well.

Example 10 and Comparative Example 10
The double carbonylation reaction was carried out in a microflow system (Example 10) and a batch system (Comparative Example 10). The reaction conditions and results are shown below. In the microflow system, the reaction proceeded well.

Example 11 and Comparative Example 11
Stille carbonylation reaction was performed in a microflow system (Example 11) and a batch system (Comparative Example 11). The reaction conditions and results are shown below. In the microflow system, the reaction proceeded well.

The schematic of the apparatus used by this invention. Sectional drawing of a micromixer.

Explanation of symbols

11: Container for substrate 21: Container for catalyst solution 31: Carbon monoxide cylinder 31
41, 42: T-shaped mixer 43: Microchannel reactor 43
45: Product container 45

Claims (4)

In the microflow mode, in the presence of a solvent and a transition metal catalyst, the formula:
R ¹ -X
[Wherein, R ¹ is a monovalent organic group, and X is a group capable of leaving R ¹ . ]
A method for producing a carbonyl compound by reacting a substrate represented by formula (II) with carbon monoxide. ^Formula: R 2 -Y
[Wherein R ² is a monovalent organic group, and Y is a group capable of leaving R ² . ]
There is also a second substrate represented by the formula:
R ¹ —C (═O) —R ²
The method of Claim 1 which produces | generates the carbonyl compound shown by these.   The method of claim 1, wherein the solvent is an ionic liquid. The process according to claim 1, wherein the transition metal catalyst is dissolved in a solvent.

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