JP7168161B2 - Method for producing heterol multimer - Google Patents

Description

The present invention relates to a method for producing heterol multimers.

A compound in which the methylene moiety of cyclopentadiene is replaced with an element other than carbon is called a heterool, and is used as a drug or organic semiconductor material, and the development of its synthesis method is underway. In particular, many heterool multimers, in which two or more heterols are linked by carbon-carbon bonds, have been reported to exhibit properties due to extension of the π-conjugated system (Non-Patent Document 1, etc.).

As a method for producing a heterool multimer, as represented by the following reaction formula, a method is known in which a reactive functional group is introduced into a raw material molecule in advance at a site for forming a bond, and then coupling is performed using a noble metal catalyst. (Ullmann coupling, Suzuki-Miyaura coupling, oxidative coupling, etc.).

In addition, as an example using a noble metal catalyst such as a palladium catalyst, there are also reports of oxidative homocoupling represented by the following reaction formula (Non-Patent Documents 2 and 3).

On the other hand, coupling using an inexpensive copper reagent in the presence of butyllithium has also been reported (Non-Patent Document 4).

Chem. Sci. 2015, 6(1), p. 360-371. React. Kinet. Catal. Lett. 1976, 5(4), p. 415-419. Synthesis. 1984, (3), 255-256. Angew. Chem. Int. Ed. Engl. 1974, 13, 291.

In the synthesis of heterool multimers, there is a problem that a method in which a reactive functional group needs to be introduced in advance to a predetermined site of a heterol to form a bond is not suitable for inexpensive large-scale synthesis. In addition, the introduced functional group must be finally disposed of as a by-product, which is disadvantageous in terms of atom economy.
In addition, in oxidative homocoupling using a palladium catalyst (Non-Patent Documents 2 and 3), the yield is limited to about 60% due to the generation of a large amount of oxidative decomposition products, and purification is difficult. , and the need to use precious metal reagents.
Furthermore, in the coupling method using an inexpensive copper reagent in the presence of butyllithium (Non-Patent Document 4), the yield remains at about 40%.
From these things, in this invention, it is cheap and makes it a subject to provide the method of manufacturing a heterol multimer with a high yield.

As a result of intensive studies to solve the above problems, the present inventors have found that heterool can be obtained at low cost and in high yield by using a heterol deprotonation accelerator in the step of deprotonating heterool, which is a raw material molecule. The inventors have found that it is possible to produce multimers, and have completed the present invention.
As used herein, heterool is a general term for compounds in which the methylene portion of cyclopentadiene is replaced with an element other than carbon (this is also referred to as a heterol skeleton), and some of the hydrogens constituting the compound are other substituents It also includes those (derivatives) replaced with. In addition, the heterool multimer refers to a carbon-carbon bond between the α-position carbon of one heteromolecule and the α-position carbon of another molecule of heterol, at least two It refers to those having the above heterol skeleton.

The present invention comprises a step of deprotonating a heterol in the presence of a heterol deprotonating agent and a deprotonation accelerator, and a coupling step in which a carbon-carbon bond is formed between the deprotonated heterols. , provides a method for the production of heterol multimers.

［式（１）及び（２）中、ＥはＯ、Ｓ、Ｓｅ、またはＴｅであり、
式（１）中、
Ｒ^１は、炭素数１～１６のアルキル、炭素数２～６のアルケニル、炭素数２～６のアルキニル、炭素数３～６のシクロアルキル、または炭素数６～１４のアリールであり、
前記炭素数１～１６のアルキルを構成する水素の少なくとも一つがＲ^２により置換されていてもよく、前記アルキルを構成する－ＣＨ_２－の少なくとも一つが、－ＣＯＯ－、－ＣＯＮＨ－、－Ｏ－、－Ｓ－、－Ｓｅ－、－Ｃ＝Ｎ－、または－ＮＨ－で置換されていてもよく、ただし、－ＣＯＯ－、－ＣＯＮＨ－、－Ｏ－、－Ｓ－、－Ｓｅ－、または－ＮＨ－が、それぞれ連続することはなく、前記Ｒ^１のアルキルの末端を構成する－ＣＨ_３が－ＮＨＣＯＯ－Ｒ^３、－ＣＯＮＨ－Ｒ^３、－Ｃ＝Ｎ－Ｒ^３、－Ｓｉ（Ｒ^３）_３で置換されてもよく、
炭素数２～８のアルケニル及び炭素数２～８のアルキニルを構成する少なくとも一つの水素が、Ｒ^２により置換されていてもよく、
前記炭素数３～６のシクロアルキルを構成する水素の少なくとも一つがＲ^２により置換されていてもよく、シクロアルキルを構成する－ＣＨ_２－の少なくとも一つが、－Ｏ－で置換されていてもよく、
前記炭素数６～１４のアリールを構成する水素の少なくとも一つがＲ^２により置換されていてもよく、
前記Ｒ^２は、炭素数１～６のアルキル、炭素数６～１４のアリール、シアノ、ニトロ、シリル、ヒドロキシル、アミノ、又はハロゲン原子を表し、
前記Ｒ^３は、水素または炭素数１～５のアルキルを表し、
ｎ１は０～３の整数であり、
式（２）中、
前記Ｒ^４は式（１）のＲ^１と同じであり、
前記Ｒ^５は、脂肪族環または芳香族環を表し、脂肪族環または芳香族環を構成する水素の少なくとも一つが、炭素数１～６のアルキル、炭素数６～１４のアリール、シアノ、ニトロ、アミド、シリル、エステル、又はハロゲン原子により置換されていてもよく、該脂肪族環を構成する－ＣＨ_２－の少なくとも一つが、－Ｏ－で置換されてもよく、ただし、－Ｏ－が連続することはなく、
ｎ２は０～２の整数である。］ Moreover, this invention provides the manufacturing method of the heterol multimer whose heterol is a compound represented by the following formula (1) or (2), or these multimers as one Embodiment.

[In formulas (1) and (2), E is O, S, Se, or Te;
In formula (1),
R ¹ is alkyl having 1 to 16 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 14 carbon atoms;
At least one hydrogen composing the alkyl having 1 to 16 carbon atoms may be substituted with R ² , and at least one of —CH ₂ — composing the alkyl is —COO—, —CONH—, —O optionally substituted with -, -S-, -Se-, -C=N-, or -NH-, with the proviso that -COO-, -CONH-, -O-, -S-, -Se-, or —NH— are not consecutive, and —CH ₃ constituting the terminal of the alkyl of R ¹ is —NHCOO—R ³ , —CONH—R ³ , —C═N—R ³ , —Si( optionally substituted with R ³ ) ₃ ;
at least one hydrogen constituting alkenyl having 2 to 8 carbon atoms and alkynyl having 2 to 8 carbon atoms may be substituted with R ² ,
At least one hydrogen constituting the cycloalkyl having 3 to 6 carbon atoms may be substituted with R ² , and at least one —CH ₂ — constituting the cycloalkyl may be substituted with —O—. Often,
at least one hydrogen constituting the aryl having 6 to 14 carbon atoms may be substituted with R ² ,
R ² represents alkyl having 1 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cyano, nitro, silyl, hydroxyl, amino, or a halogen atom;
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
n1 is an integer from 0 to 3,
In formula (2),
R ⁴ is the same as R ¹ in formula (1),
R ⁵ represents an aliphatic ring or an aromatic ring, and at least one hydrogen constituting the aliphatic or aromatic ring is alkyl having 1 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cyano, or nitro. , amide, silyl, ester, or a halogen atom, and at least one —CH ₂ — constituting the aliphatic ring may be substituted with —O—, provided that —O— is not continuous,
n2 is an integer of 0-2. ]

Moreover, the present invention provides, as one embodiment, a method for producing a heterol multimer, wherein the deprotonating agent is an organic alkali metal.

In addition, as one embodiment, the present invention provides a method for producing a heterol multimer, wherein the deprotonation accelerator is a compound having coordinating ability with respect to alkali metal ions.

Moreover, the present invention provides, as one embodiment, a method for producing a heterool multimer, wherein the total time of the deprotonation step and the coupling step is 3 hours or less.

A production method according to an embodiment of the present invention includes a deprotonation step of deprotonating a heterol in the presence of a deprotonating agent and a deprotonation accelerator.
Specific examples of the deprotonating agent and the deprotonation accelerator will be described later.
The deprotonation step is a step of adding a heterol and a deprotonation accelerator to a suitable solvent in the presence of an inert gas such as nitrogen, and further adding a deprotonation agent to react them.
An example of the temperature at which the deprotonating agent is added is -100 to -20°C. Another example of the temperature is -80 to -20°C, and another example is -30 to -10°C. In the embodiment of the present invention, by using a deprotonation accelerator, the reaction proceeds with high efficiency, so that the reaction in the process, which was conventionally thought to have to be performed at low temperature, can be performed at a higher temperature than before. It has been found that it can be done.

In addition, in the method for producing a heterol multimer according to the embodiment of the present invention, not only a heterol monomer but also a heterol multimer can be used as a raw material for synthesizing the multimer. For example, when heterol dimers are used as starting materials, heterol tetramers can be synthesized. Further, by using a heterol monomer and a heterol dimer as starting materials, a mixture of a heterol dimer, a trimer and a tetramer can be obtained.

<Deprotonating agent for heterol>
The heterol deprotonating agents used in embodiments of the present invention are those that cause deprotonation of the carbon at the alpha position of the heterol.
Specific examples of heterol deprotonating agents include organic alkali metals. An alkyl lithium can be mentioned as an organic alkali metal.
Examples of alkyllithium that can be used include ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, s-butyllithium and t-butyllithium. Among these, it is preferable to use n-butyllithium.
In the heterol deprotonation step, the molar ratio of the heterol used as a substrate and the heterol deprotonating agent can be 1:1 to 1:10, and 1:1 to 1:3. preferably 1:1 to 1:1.5.

<Heterol deprotonation accelerator>
The heterol deprotonation accelerator used in the production method according to the embodiment of the present invention is a compound having a coordinating ability to coordinate an alkyl metal. Such compounds may include polydentate amines or polyethers, more specifically tertiary amines or crown ethers.
Examples of the tertiary amine include at least one selected from the group consisting of tetramethylethylenediamine, trimethylamine and triethylamine. Among these, it is preferable to use tetramethylethylenediamine.
As the crown ether, dibenzo 24-crown-8-ether, dicyclohexyl 24-crown-8-ether, 24-crown-8-ether, dibenzo 18-crown-6-ether, dicyclohexyl 18-crown-6-ether, 18 -crown-6-ether, benzo 12-crown-4-ether, cyclohexyl 12-crown-4-ether, and at least one selected from the group consisting of 12-crown-4-ether. Among these, 12-crown-4-ether is preferably used.
In the production method according to the embodiment of the present invention, by using a heterol deprotonation accelerator, it is possible to prevent association during the reaction of the heterol deprotonation agent, thereby facilitating the heterol deprotonation reaction. can do.
In the heterol deprotonation step, the molar ratio of the heterol deprotonating agent to the heterol deprotonation accelerator can be 1:0.5 to 1:5.
A ratio of 0.9 to 1:1 is preferred.

A production method according to an embodiment of the present invention includes, after the deprotonation step described above, a coupling step in which a carbon-carbon bond is formed between the protonated heterools.
The coupling step is a step of coupling the deprotonated heterools to form a carbon-carbon bond.
A suitable coupling reagent is used for the coupling. Coupling reagents include, for example, reagents containing copper. Copper-containing reagents include copper (II) chloride, copper (I) chloride, copper (II) bromide, copper (I) bromide, copper (II) iodide, copper (I) iodide, copper acetate ( II) can be mentioned. Since these reagents containing copper are inexpensive, they can be preferably used for the inexpensive production of heterol multimers.
Conditions for the coupling reaction include -100°C to room temperature, preferably -80°C to -30°C.

The deprotonation step and the coupling step described above are preferably performed continuously in the same system from the viewpoint of inexpensive production of the heterool multimer.
In addition, according to the present invention, the total reaction time of the deprotonation step and the coupling step can be as short as 0.5 to 3 hours. It can also be done in terms of time. In the conventional method, the yield was only about 40% even after a long reaction time of 12 hours. Embodiments of the present invention can reduce reaction times by as much as 75% or more compared to previous methods (without deprotonation accelerators).

The above deprotonation step and coupling step can be carried out in an organic solvent. Examples of organic solvents include haloalkanes such as dichloromethane, chloroform, and carbon tetrachloride; carbonyl esters having no α proton such as phenylbenzoic acid; alkylbenzenes such as toluene; ethers such as diethyl ether and tetrahydrofuran; Alternatively, a mixed solvent thereof can be used. The amount of the organic solvent to be used is not particularly limited, but it can usually be used in an amount of about 0.5 to 30 times the weight of the heterool.
After completion of the reaction, normally, in addition to filtration, concentration, etc., washing (washing with water, acid or alkali washing, etc.), extraction, distillation, recrystallization, column chromatography, etc. are used to separate and purify the desired product. A heterol multimer is obtained, but the production method according to the embodiment of the present invention can obtain a heterol derivative in high yield and has few by-products, so it can be purified only by filtration, concentration, or separation and purification of precipitation. is.

Hereinafter, heterools that can be used in the production of heterol multimers in embodiments of the present invention will be described. In formulas (1) and (2) above, E is O, S, Se, or Te.

In formula (1) above, R ¹ is preferably alkyl having 1 to 16 carbon atoms or cycloalkyl having 3 to 6 carbon atoms.
When R ¹ is C 1-16 alkyl, linear, branched or cyclic C 1-6 alkyl can be mentioned. At least one of —CH ₂ — constituting the alkyl may be substituted with —COO—, —CONH—, —O—, —S—, —Se—, or —NH—, with the proviso that —O -, -S-, -Se-, -C=N-, or -NH- are not consecutive. -CH ₂ - of alkyl substituted with -COO-, -CONH-, -O-, -S-, -Se- or -NH- may be bonded to a carbon constituting a heterool .
Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. At least one of the hydrogen atoms constituting these groups may be substituted with cyano, nitro, silyl, hydroxy, amino, or halogen atoms.
When R ¹ is alkyl having 1 to 16 carbon atoms, —CH ₃ constituting the terminal of the alkyl is —NHCOO—R ³ , —CONH—R ³ , —C═N—R ³ , or —O—Si It is preferably substituted with (R ³ ) ₃ . When —CH ₃ constituting the terminal of alkyl is substituted with —NHCOO—R ³ , —CONH—R ³ , or —C═N—R ³ , R ³ is methyl, ethyl, propyl or tert-butyl. is preferred, and tert-butyl is more preferred.
When —CH ₃ constituting the alkyl terminal is substituted with —O—Si(R ³ ) ₃ , R ³ is preferably independently methyl, ethyl, propyl, tert-butyl, and 2 More preferably, one R ³ is methyl and one R ³ is tert-butyl.

When R ¹ is C 3-6 cycloalkyl, examples include cyclobutyl, cyclopentyl and cyclohexyl. Further, when R ¹ is a cycloalkyl having 3 to 6 carbon atoms, at least one —CH ₂ — constituting the cycloalkyl is preferably substituted with —O—, and two —CH ₂ — is more preferably substituted with -O-. Specifically, when one of —CH ₂ — is substituted with —O—, glycidyl can be mentioned, and when two are substituted with —O—, 1,4-dioxanyl, 1,3 -dioxolanyl, 1,3-dioxolanyl, preferably 1,3-dioxolanyl.

When R ¹ is alkenyl having 2 to 8 carbon atoms, vinyl, allyl, butadienyl, hexatrienyl, octatetraenyl, cyclohexenyl, cyclohexadienyl and the like can be mentioned, and at least one hydrogen constituting these is It may be substituted with alkyl having 1 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cyano, nitro, amido, silyl, ester or halogen atom.

When R ¹ is alkynyl having 2 to 8 carbon atoms, examples thereof include ethynyl, propargyl, butadiynyl, hexatriynyl, etc., and at least one hydrogen constituting these is alkyl having 1 to 6 carbon atoms and 6 carbon atoms. optionally substituted with ˜14 aryl, cyano, nitro, amido, silyl, ester, or halogen atoms.

In formula (1), n1 is an integer of 0-3. n1 is preferably 0 or 1.

In formula (2), ^R4 is the same as ^R1 .
In formula (2), R ⁵ is an aliphatic ring or an aromatic ring, and when R ⁵ is an aliphatic ring, monocyclic or bicyclic or more cycloalkanes can be mentioned, such as cyclopropane, cyclobutane, Cyclopentane, cyclohexane and the like can be mentioned. Also, at least one hydrogen atom constituting the aliphatic ring may be substituted with a cyano, nitro, amido, silyl, ester, or halogen atom.
When R ⁵ is an aromatic ring, it may be a monocyclic or bicyclic aromatic ring, specifically benzene, naphthalene, anthracene, phenanthrene, and the like. Also, at least one hydrogen atom constituting the aromatic ring may be substituted with a cyano, nitro, amido, silyl, ester, or halogen atom.
In formula (2), n2 is an integer of 0-2. n1 is preferably 0 or 1.

（式（３）中のＥおよびＲ^１は式（１）の説明（好ましい例示も含む）と同じである。ｎ_３及びｎ_５は、独立して０～２の整数であり、ｎ_４は、０または１である。ｘは０以上の整数である。式（３）において、Ｒ^１はそれぞれ同一であっても異なっていてもよい。）
上記式（３）で表される化合物の具体例として、以下の式（４）で表される化合物を挙げることもできる。

（式（４）中のＲ^１は式（１）の説明と同じである。ｎ_１は０～２の整数である。式（４）において、Ｒ^１とｎ_１は、それぞれ同一であっても異なっていてもよい。）
もちろん、上記の（３）や（４）で表されるヘテロールにさらに別のヘテロール（例えば式（２）で表されるヘテロールなど）が結合した多量体を、本発明の製造方法の原料として用いることもできる。また、式（２）で表されるヘテロールのみから構成される多量体も原料として用いることができる。 Heterols that can be used in synthesizing a multimer may be one of the above-described heterols, or two or more of them can be used. Moreover, as described above, when synthesizing a multimer, not only the heterol monomer described above but also a dimer or higher multimer may be used. For example, among the compounds represented by the above formula (1), multimers in which two or more heterols having the same or different structures are bonded can be used as a starting material. Specific examples of such multimers include those having a structure represented by (3) below.

(E and R ¹ in formula (3) are the same as described in formula (1) (including preferred examples). n ₃ and n ₅ are independently integers of 0 to 2, and n ₄ is , 0 or 1. x is an integer greater than or equal to 0. In formula (3), each R ¹ may be the same or different.)
As a specific example of the compound represented by the above formula (3), a compound represented by the following formula (4) can also be mentioned.

(R ¹ in formula (4) is the same as in formula (1). n ₁ is an integer of 0 to 2. In formula (4), R ¹ and n ₁ are the same and may be different.)
Of course, a multimer in which another heterol (for example, a heterol represented by formula (2)) is bound to the above heterol represented by (3) or (4) is used as a raw material for the production method of the present invention. can also In addition, a multimer composed only of a heterol represented by formula (2) can also be used as a raw material.

A method for producing a heterol multimer according to embodiments of the present invention will be described below, but the present invention is not limited by these examples.

窒素気流下でシュレンクチューブに２－（２－フリル）－１，３－ジオキソラン（０．５ｍＬ、４．２５ｍｍｏｌ）、ＴＨＦ（２０ｍＬ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン（０．７ｍＬ、４．３２ｍｍｏｌ）を加えた。その後、－７８℃に冷却し、ｎ－ＢｕＬｉ（２．９ｍＬ、１．６Ｍ、４．６４ｍｍｏｌ）を添加し、－７８℃で３０分撹拌した。－７８℃を保持したまま、ＣｕＣｌ_２（０．６８８ｇ、５．１２ｍｍｏｌ）を添加した。温度を室温までゆっくりと上昇させた後、１時間還流を行った。反応終了後、溶液を室温に戻したら飽和ＮＨ_４Ｃｌ水溶液を添加し、有機層をジクロロメタンで抽出した。得られた有機層を飽和ＮＨ_４Ｃｌ水溶液と蒸留水で洗浄し、ＭｇＳＯ_４で乾燥を行った後、濾過を行い、溶液を濃縮することでオレンジ色の固体と油状物質の混合物を得た。この混合物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製することで［２，２’－ビフラン］－５，５’－ジ（１，３－ジオキソラン）を淡黄色固体して得た（０．５５８ ｇ、２．０１ｍｍｏｌ、９５％）。
¹H NMR (400 MHz, CDCl₃): 6.54 (d, J = 3.2 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H), 5.96 (s, 1H), 4.16-4.10 (m, 2H), 4.07-4.01 (m, 2H).
なお、¹H NMRの測定は、ＪＥＯＬ製 ＪＮＭ－ＡＣＸ４００を用いて行った。以下の実施例も同様である。 <Example 1>
Synthesis of [2,2′-bifuran]-5,5′-di(1,3-dioxolane)

2-(2-Furyl)-1,3-dioxolane (0.5 mL, 4.25 mmol), THF (20 mL), N,N,N',N'-tetramethylethylenediamine (0 .7 mL, 4.32 mmol) was added. It was then cooled to -78°C, n-BuLi (2.9 mL, 1.6 M, 4.64 mmol) was added and stirred at -78°C for 30 minutes. CuCl ₂ (0.688 g, 5.12 mmol) was added while maintaining −78° C. After slowly raising the temperature to room temperature, the mixture was refluxed for 1 hour. After completion of the reaction, the solution was returned to room temperature, a saturated NH ₄ Cl aqueous solution was added, and the organic layer was extracted with dichloromethane. The resulting organic layer was washed with a saturated NH ₄ Cl aqueous solution and distilled water, dried over MgSO ₄ , filtered, and the solution was concentrated to obtain a mixture of an orange solid and an oily substance. This mixture was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give [2,2'-bifuran]-5,5'-di(1,3-dioxolane) as a pale yellow solid. Obtained (0.558 g, 2.01 mmol, 95%).
¹ H NMR (400 MHz, CDCl ₃ ): 6.54 (d, J = 3.2 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H), 5.96 (s, 1H), 4.16-4.10 (m, 2H) , 4.07-4.01 (m, 2H).
¹ H NMR was measured using JNM-ACX400 manufactured by JEOL. The same applies to the following examples.

窒素気流下でシュレンクチューブに２－（２－チエニル）－１，３－ジオキソラン（０．５０ｍＬ、３．９７ｍｍｏｌ）、ＴＨＦ（２０ｍＬ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン（０．６０ｍＬ、４．０２ｍｍｏｌ）を加えた。その後、－７８℃に冷却し、ｎ－ＢｕＬｉ（２．７ｍＬ、１．６Ｍ、４．３７ｍｍｏｌ）を添加し、－７８℃で１時間撹拌した。－７８℃を保持したまま、ＣｕＣｌ_２（０．６４３ｇ、４．７７ｍｍｏｌ）を添加した。温度を室温までゆっくりと上昇させた後、１時間還流を行った。反応終了後、溶液を室温に戻したら飽和ＮＨ_４Ｃｌ水溶液を添加し、有機層をジクロロメタンで抽出した。得られた有機層を飽和ＮＨ_４Ｃｌ水溶液と蒸留水で洗浄し、ＭｇＳＯ_４で乾燥を行った後、濾過を行い、溶液を濃縮することでオレンジ色の固体油状物質の混合物を得た。この混合物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製することで［２，２’－ビフラン］－５，５’－ジ（１，３－ジオキソラン）を淡黄色固体して得た（０．５９４ｇ、１．９２ｍｍｏｌ、９６％）。
¹H NMR (400 MHz, CDCl₃): 7.06 (d, J = 3.6 Hz, 2H), 7.03 (d, J = 3.6 Hz, 2H), 6.07 (s, 1H), 4.17-4.11 (m, 2H), 4.07-4.01 (m, 2H). <Example 2>
Synthesis of [2,2′-bithiophene]-5,5′-di(1,3-dioxolane)

2-(2-Thienyl)-1,3-dioxolane (0.50 mL, 3.97 mmol), THF (20 mL), N,N,N',N'-tetramethylethylenediamine (0 .60 mL, 4.02 mmol) was added. It was then cooled to -78°C, n-BuLi (2.7 mL, 1.6 M, 4.37 mmol) was added and stirred at -78°C for 1 hour. CuCl ₂ (0.643 g, 4.77 mmol) was added while maintaining -78°C. After slowly raising the temperature to room temperature, the mixture was refluxed for 1 hour. After completion of the reaction, the solution was returned to room temperature, a saturated NH ₄ Cl aqueous solution was added, and the organic layer was extracted with dichloromethane. The resulting organic layer was washed with a saturated NH ₄ Cl aqueous solution and distilled water, dried over MgSO ₄ , filtered, and the solution was concentrated to obtain a mixture of orange solid oily substances. This mixture was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give [2,2'-bifuran]-5,5'-di(1,3-dioxolane) as a pale yellow solid. Obtained (0.594 g, 1.92 mmol, 96%).
¹ H NMR (400 MHz, CDCl ₃ ): 7.06 (d, J = 3.6 Hz, 2H), 7.03 (d, J = 3.6 Hz, 2H), 6.07 (s, 1H), 4.17-4.11 (m, 2H) , 4.07-4.01 (m, 2H).

窒素気流下でシュレンクチューブに２－（３－フリル）－１，３－ジオキソラン（０．５ ｍＬ，４．２５ｍｍｏｌ）、ＴＨＦ（２０ｍＬ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチ
ルエチレンジアミン（０．７ｍＬ、４．３２ｍｍｏｌ）を加えた。その後、－７８℃に冷却し、ｎ－ＢｕＬｉ（３．０ｍＬ、１．６Ｍ、４．８０ｍｍｏｌ）を添加し、－７８℃で１時間撹拌した。－７８℃を保持したまま、ＣｕＣｌ_２（０．７４ｇ、５．５０ｍｍｏｌ）を添加した。温度を室温までゆっくりと上昇させた後、１時間還流を行った。反応終了後、溶液を室温に戻したら飽和ＮＨ_４Ｃｌ水溶液を添加し、有機層をジクロロメタンで抽出した。得られた有機層を飽和ＮＨ_４Ｃｌ水溶液と蒸留水で洗浄し、ＭｇＳＯ_４で乾燥を行った後、濾過を行い、溶液を濃縮することでオレンジ色の固体油状物質の混合物を得た。この混合物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製することで［２，２’－ビフラン］－４，４’－ジ（１，３－ジオキソラン）を淡黄色固体して得た（０．５５９ｇ、２．０１ｍｍｏｌ、９５％）。
¹H NMR (400 MHz, CDCl₃): 6.54 (d, J = 3.2 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H), 5.96 (s, 1H), 4.16-4.10 (m, 2H), 4.07-4.01 (m, 2H). <Example 3>
Synthesis of [2,2′-bifuran]-4,4′-di(1,3-dioxolane)

2-(3-furyl)-1,3-dioxolane (0.5 mL, 4.25 mmol), THF (20 mL), N,N,N',N'-tetramethylethylenediamine ( 0.7 mL, 4.32 mmol) was added. It was then cooled to -78°C, n-BuLi (3.0 mL, 1.6 M, 4.80 mmol) was added and stirred at -78°C for 1 hour. CuCl ₂ (0.74 g, 5.50 mmol) was added while maintaining -78°C. After slowly raising the temperature to room temperature, the mixture was refluxed for 1 hour. After completion of the reaction, the solution was returned to room temperature, a saturated NH ₄ Cl aqueous solution was added, and the organic layer was extracted with dichloromethane. The resulting organic layer was washed with a saturated NH ₄ Cl aqueous solution and distilled water, dried over MgSO ₄ , filtered, and the solution was concentrated to obtain a mixture of orange solid oily substances. This mixture was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give [2,2'-bifuran]-4,4'-di(1,3-dioxolane) as a pale yellow solid. Obtained (0.559 g, 2.01 mmol, 95%).
¹ H NMR (400 MHz, CDCl ₃ ): 6.54 (d, J = 3.2 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H), 5.96 (s, 1H), 4.16-4.10 (m, 2H) , 4.07-4.01 (m, 2H).

窒素気流下でシュレンクチューブにフラン（０．５ｍＬ、６．８８ｍｍｏｌ）、ＴＨ
Ｆ（２０ｍＬ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン（１．１ｍＬ、７．３８ｍｍｏｌ）を加えた。その後、－７８℃に冷却し、ｎ－ＢｕＬｉ（４．８ｍＬ、１．６Ｍ、７．６８ｍｍｏｌ）を添加し、－７８℃で３０分撹拌した。－７８℃を保持したまま、ＣｕＣｌ_２（１．１１ｇ、８．２６ｍｍｏｌ）を添加した。温度を室温までゆっくりと上昇させた後、１２時間撹拌を行った。反応終了後、溶液を室温に戻したら飽和ＮＨ_４Ｃｌ水溶液を添加し、有機層をジクロロメタンで抽出した。得られた有機層を飽和ＮＨ_４Ｃｌ水溶液と蒸留水で洗浄し、ＭｇＳＯ_４で乾燥を行った後、濾過を行い、溶液を濃縮することでオレンジ色の固体油状物質の混合物をオレンジ色油状物質として得た（０．４
４２ｇ、３．３０ｍｍｏｌ、８３％）。
¹H NMR (400 MHz, CDCl₃): 7.41 (d, J = 1.6 Hz, 2H), 6.56 (d, J = 3.6 Hz, 2H), 6.46 (dd, J = 4.8 Hz, J = 1.6 Hz,2H). <Example 4>
Synthesis of [2,2′-bifuran]

Furan (0.5 mL, 6.88 mmol), TH
F (20 mL), N,N,N',N'-tetramethylethylenediamine (1.1 mL, 7.38 mmol) were added. It was then cooled to -78°C, n-BuLi (4.8 mL, 1.6 M, 7.68 mmol) was added and stirred at -78°C for 30 minutes. CuCl ₂ (1.11 g, 8.26 mmol) was added while maintaining −78° C. After slowly raising the temperature to room temperature, stirring was carried out for 12 hours. After completion of the reaction, the solution was returned to room temperature, a saturated NH ₄ Cl aqueous solution was added, and the organic layer was extracted with dichloromethane. The resulting organic layer was washed with a saturated NH ₄ Cl aqueous solution and distilled water, dried over MgSO ₄ , filtered, and the solution was concentrated to convert a mixture of an orange solid oily substance into an orange oily substance. (0.4
42 g, 3.30 mmol, 83%).
¹ H NMR (400 MHz, CDCl ₃ ): 7.41 (d, J = 1.6 Hz, 2H), 6.56 (d, J = 3.6 Hz, 2H), 6.46 (dd, J = 4.8 Hz, J = 1.6 Hz, 2H ).

窒素気流下でシュレンクチューブに２－メチル－フラン（０．５ｍＬ、５．６５ｍｍｏｌ）、ＴＨＦ（２０ｍＬ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン（０．９ ｍＬ、６．０４ｍｍｏｌ）を加えた。その後、－７８℃に冷却し、ｎ－ＢｕＬｉ（５
．４ｍＬ、１．６Ｍ、８．６４ｍｍｏｌ）を添加し、－７８℃で１時間撹拌した。－７８℃を保持したまま、ＣｕＣｌ_２（０．７６４ｇ、５．６８ｍｍｏｌ）を添加した。温度を室温までゆっくりと上昇させた後、１２時間撹拌を行った。反応終了後、溶液を室温に戻したら飽和ＮＨ_４Ｃｌ水溶液を添加し、有機層をジクロロメタンで抽出した。得られた有機層を飽和ＮＨ_４Ｃｌ水溶液と蒸留水で洗浄し、ＭｇＳＯ_４で乾燥を行った後、濾過を行い、溶液を濃縮することでオレンジ色の固体油状物質の混合物をオレンジ色油状物質として得た（０．４５５ｇ、２．３３ｍｍｏｌ、８２％）。
¹H NMR (400 MHz, CDCl₃): 6.36 (d, J = 3.2 Hz, 2H), 6.56 (d, J = 2.8 Hz, 2H), 2.34 (s, 6H). <Example 5>
Synthesis of 5,5'-dimethyl-2,2'-bifuran

2-Methyl-furan (0.5 mL, 5.65 mmol), THF (20 mL), N,N,N',N'-tetramethylethylenediamine (0.9 mL, 6.04 mmol) in a Schlenk tube under a nitrogen stream. was added. After that, it is cooled to −78° C. and n-BuLi (5
. 4 mL, 1.6 M, 8.64 mmol) was added and stirred at −78° C. for 1 hour. CuCl ₂ (0.764 g, 5.68 mmol) was added while maintaining -78 °C. After slowly raising the temperature to room temperature, stirring was carried out for 12 hours. After completion of the reaction, the solution was returned to room temperature, a saturated NH ₄ Cl aqueous solution was added, and the organic layer was extracted with dichloromethane. The resulting organic layer was washed with a saturated NH ₄ Cl aqueous solution and distilled water, dried over MgSO ₄ , filtered, and the solution was concentrated to convert a mixture of an orange solid oily substance into an orange oily substance. (0.455 g, 2.33 mmol, 82%).
¹ H NMR (400 MHz, CDCl ₃ ): 6.36 (d, J = 3.2 Hz, 2H), 6.56 (d, J = 2.8 Hz, 2H), 2.34 (s, 6H).

<Comparative Example 1>
[2,2′-bifuran]-5,5′-di(1,2′-bifuran]-5,5′-di(1,2′-bifuran)-5,5′-di(1,2′-bifuran]-5,5′-di(1,2′-bifuran)-5,5′-di(1, 3-dioxolane) was synthesized (yield 53%). The synthesis method of this comparative example conforms to the method described in Non-Patent Document 4.

The results of Examples 1 to 5 and Comparative Example 1 are summarized in Table 1. When the production method of the present invention was used, a heterool multimer could be obtained in a high yield in a short reaction time. In particular, the results of Example 1 and Comparative Example 1 show that it is very important to use the deprotonation accelerator used in the present invention. In Comparative Example 1, although the reaction time was 20 hours or longer, only a low yield was obtained. In addition, in the present invention, the reaction is caused using a deprotonating agent typified by a copper-containing compound without using the palladium catalyst used in the Suzuki-Miyaura coupling, so that heterool multimers can be obtained at low cost.
In addition, it was found that side reactions hardly occur in the method for producing heterol multimers of the present invention.
Furthermore, as is clear from Examples 1 and 2, it was found that furan is not the only heterool capable of obtaining high-yield multimers (thiophene and the like can also be used). Therefore, the method for producing a heterol multimer of the present invention can be applied to various heterools.
Moreover, as is clear from Examples 1 and 3, according to the production method of the present invention, a heterool multimer can be obtained in high yield even if the positions of the substituents to which the heterools are bonded are different.
Furthermore, as shown in Examples 4 and 5, according to the production method of the present invention, even if the heterol is unsubstituted or the substituent of the heterol is different from that in Example 1, the yield is high. heterolol multimers can be obtained.

The heterool multimer produced by the production method of the present invention is expected to have an intercalation effect on DNA, and thus is expected to be applied to pharmaceuticals. Moreover, the heterool multimer produced by the production method of the present invention can be expected to be applied to organic semiconductor materials such as organic thin-film solar cells, organic ELs, and organic transistors. In addition, the heterool polymer produced by the production method of the present invention can also be expected to be applied to engineering plastics such as polyesters, polyamides, polyimides and polycarbonates.

Claims (2)

A deprotonation step of deprotonating the heterool in the presence of a heterol deprotonating agent and a deprotonation accelerator, and a coupling step of forming a carbon-carbon bond between the deprotonated heterols. A method for producing a heterol dimer , comprising:
the deprotonating agent is butyl lithium;
The deprotonation accelerator is tetramethylethylenediamine,
The production method, wherein the heterool is a compound represented by the following formula (1).

[In the formula (1), E is O,
R ¹ is alkyl having 1 to 16 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms,
quinyl, cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 14 carbon atoms,
at least one hydrogen composing the alkyl having 1 to 16 carbon atoms is substituted with R ²
at least one of —CH ₂ — constituting the alkyl may be —COO—, —
optionally substituted with CONH-, -O-, -S-, -Se-, -C=N-, or -NH-, with the proviso that -COO-, -CONH-, -O-, -S- , —Se—, or —NH— are not consecutive, and —CH ₃ constituting the alkyl terminal of R ¹ is —NHCOO—R ³ , —CONH—R ³ , —C═N— R ³ , optionally substituted with —Si(R ³ ) ₃
,
at least one hydrogen constituting alkenyl having 2 to 8 carbon atoms and alkynyl having 2 to 8 carbon atoms may be substituted with R ² ,
at least one hydrogen constituting the cycloalkyl having 3 to 6 carbon atoms is replaced with R ²
at least one of —CH ₂ — constituting cycloalkyl is —O—
may be substituted,
at least one hydrogen composing the aryl having 6 to 14 carbon atoms is substituted with R ²
may be
R ² is alkyl having 1 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cyano, nitro,
represents a silyl, hydroxy, amino, or halogen atom,
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
n1 is an integer from 0 to 1; ] 2. The method for producing a heterool dimer according to claim 1 , wherein the total time of the deprotonation step and the coupling step is 3 hours or less.