Photochemical synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes

Abstract

A method for producing 1,3-disubstituted bicyclo[1.1.1]pentanes which allow the co-existence of a cyclic ether compound in a reaction solution when obtaining a 1,3-disubstituted bicyclo[1.1.1]pentane by causing [1.1.1]propellane and a 1,2-diketone compound to undergo a photoreaction in a solvent containing a non-cyclic ether solvent having five or more carbon atoms.

Description

[Technical field]

[0001] The present invention relates to a method for producing 1,3-disubstituted bicyclo[1.1.1]pentanes by photoreaction. [Background technology]

[0002] Bicyclo[1.1.1]pentane (BCP) compounds have attracted attention as biologically active compounds. The BCP motif has the same biofunctionality as para-substituted phenyl, alkynyl, and tert-butyl groups, while being highly three-dimensional and biologically safe, and is therefore expected to be useful in drug delivery. 1,3-disubstituted BCPs have been introduced as building blocks in the synthesis of candidate pharmaceutical compounds. A method is known in which [1.1.1]propellane and a 1,2-diketone compound are subjected to a photoreaction to obtain a 1,3-disubstituted BCP. For example, Patent Document 1 describes a method for synthesizing 1,3-diacetyl BCP by subjecting [1.1.1]propellane and 2,3-butanedione to a photoreaction. Patent Document 2 describes the photoreaction of [1.1.1]propellane and a glyoxylic acid compound to obtain a 1,3-disubstituted BCP. [Prior art documents] [Non-patent literature]

[0003] [Patent Document 1] Special Publication No. 2020-533330 [Patent Document 2] Special Publication No. 2019-510012 Summary of the Invention [Problem to be solved by the invention]

[0004] An objective of the present invention is to provide a method for producing 1,3-disubstituted BCP, which can promote the photoreaction and produce the target 1,3-disubstituted BCP with high efficiency when the photoreaction is performed between [1.1.1]propellane and a 1,2-diketone compound to obtain 1,3-disubstituted BCP. [Means for solving the problem]

[0005] The object of the present invention has been achieved by the following means.

[0006] [1] A method for producing 1,3-disubstituted bicyclo[1.1.1]pentane, comprising photoreacting [1.1.1]propellane with a 1,2-diketone compound in a solvent containing an acyclic ether solvent having 5 or more carbon atoms to obtain 1,3-disubstituted bicyclo[1.1.1]pentane, and allowing a cyclic ether compound to coexist in the reaction solution. [2] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to [1], wherein the acyclic ether solvent has 5 to 10 carbon atoms. [3] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to [1] or [2], wherein the acyclic ether solvent has 5 or 6 carbon atoms. [4] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [3], wherein the 1,2-diketone compound is a diacetyl compound or a glyoxylic acid compound. [5] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [4], wherein the cyclic ether compound is a tetrahydrofuran compound. [6] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [5], wherein the photoreaction is carried out by irradiation with light having a wavelength of 200 to 600 nm. [7] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [6], wherein the reaction temperature of the photoreaction is −50 to 50° C.

[0007] In the present invention and the specification, a numerical range expressed using "to" means a range including the numerical values ​​before and after "to" as the lower and upper limits. Effect of the Invention

[0008] According to the method for producing 1,3-disubstituted BCP of the present invention, the photoreaction between [1.1.1]propellane and a 1,2-diketone compound can be promoted, and the target 1,3-disubstituted BCP can be obtained highly efficiently by the photoreaction. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram of a flow reaction system used in the examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In the method for producing 1,3-disubstituted BCP of the present invention (hereinafter also referred to as the production method of the present invention), [1.1.1]propellane and a 1,2-diketone compound are photoreacted in a solvent containing an acyclic ether solvent having 5 or more carbon atoms. In the production method of the present invention, a cyclic ether compound is made to coexist in the reaction solution during this photoreaction, and thus the desired 1,3-disubstituted BCP can be obtained with high efficiency. In this reaction system, the cyclic ether functions as an additive for promoting the reaction.

[0011] [Acyclic ether solvents with 5 or more carbon atoms] The acyclic ether solvent having 5 or more carbon atoms used in the production method of the present invention preferably has 5 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, even more preferably 5 to 7 carbon atoms, and even more preferably 5 or 6 carbon atoms. By using a non-cyclic ether solvent having 5 or more carbon atoms, the reaction promoting effect due to the addition of a cyclic ether can be effectively exerted. The acyclic ether solvent having 5 or more carbon atoms is more preferably at least one of cyclopentyl methyl ether and methyl tert-butyl ether.

[0012] The solvent used in the production method of the present invention may contain a solvent other than the acyclic ether having 5 or more carbon atoms (solvent other than "acyclic ether having 5 or more carbon atoms") (excluding cyclic ether compounds). The solvent other than the acyclic ether having 5 or more carbon atoms is not particularly limited, and can be appropriately used within a range that does not impair the effects of the present invention. Preferred examples of the solvent other than the acyclic ether having 5 or more carbon atoms include hydrocarbon solvents, and among them, aliphatic hydrocarbon solvents (e.g., hexane, cyclohexane, pentane, heptane, etc.) are preferred. When the acyclic ether having 5 or more carbon atoms and the other solvent are contained, the ratio of the amount of these is preferably 1 / 10 or more, more preferably 1 / 5 or more, even more preferably 1 / 2 or more, and even more preferably 1 / 1 or more, in terms of mass ratio, [acyclic ether solvent having 5 or more carbon atoms] / [solvent other than acyclic ether having 5 or more carbon atoms]. That is, the ratio of the acyclic ether solvent having 5 or more carbon atoms in the solvent is preferably 50% by mass or more, preferably 60% by mass or more, and also preferably 65% ​​by mass or more.

[0013] [[1.1.1] Propellan] [1.1.1]Propellane can generally be obtained by reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent. As the organometallic compound, a wide variety of alkyllithiums, aryllithiums, etc. can be used. The reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent to obtain [1.1.1]propellane is already known, and reference can be made, for example, to Chem. Commun., 2021, Vol. 57, pp. 2871-2874.

[0014] [1,2-diketone compounds] 1,2-diketone compounds are compounds with the structure "*-C(=O)-C(=O)-*". * indicates the linking site. 1,2-diketone compounds are easily cleaved between the two carbonyl groups by light energy, and react with [1.1.1]propellane to produce 1,3-disubstituted BCP. Examples of 1,2-diketone compounds include diacetyl compounds (2,3-butanedione compounds) and glyoxylic acid compounds. In the present invention, the term "compound" means "a compound having a skeleton". For example, the term "diacetyl compound" refers to not only diacetyl itself (2,3-butanedione itself), but also diacetyl in which at least a part of the hydrogen atoms has been replaced. The diacetyl in which at least a part of the hydrogen atoms has been replaced includes a diacetyl in which -CH3 has been changed to a structure having an unsaturated bond, such as -CH=CH2 or -CN. The diacetyl in which two or three hydrogen atoms have been replaced by substituents also includes a diacetyl in which two or three substituents are bonded to each other to form a ring.

[0015] Preferred specific examples of the diacetyl compound are shown below. In the table below, D represents deuterium.

[0016] [ka]

[0017] Preferred specific examples of the glyoxylic acid compound are given below.

[0018] [ka]

[0019] [Cyclic Ether Compounds] In the present invention, the cyclic ether compound does not act as a solvent, but is added in a small amount to function as a reaction promoter. That is, in the production method of the present invention, a non-cyclic ether solvent having 5 or more carbon atoms is used as a solvent, and the cyclic ether compound is added as an additive different from the solvent. By adding the cyclic ether compound, the reaction rate of the photoreaction specified in the present invention can be significantly accelerated, and the yield of the target 1,3-disubstituted BCP can be effectively increased. Although the reason for this is unclear, it is considered that one of the reasons is that the active species in which the two carbonyl groups of the 1,2-diketone compound are cleaved by light energy is stabilized by the cyclic ether compound, and recombination between the active species is suppressed. As shown in the examples described later, the reaction promotion effect is not observed even when various compounds other than the cyclic ether compound are added. That is, in the photoreaction specified in the present invention, the reaction promotion effect of the cyclic ether compound is unique to the cyclic ether compound and is not observed in other compounds. Preferred examples of the cyclic ether compound include tetrahydrofuran (THF) compounds (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), 2,5-dihydrofuran, tetrahydrofuran-d8 (deuterated tetrahydrofuran), 3-methyltetrahydrofuran, 2-hydroxytetrahydrofuran, 2-chlorotetrahydrofuran, etc.), tetrahydropyran, 4-methyltetrahydropyran, furan, 1,4-dioxane, etc. Among these, THF compounds are preferred, and at least one of THF and 2-methylTHF is more preferred. In the photoreaction, the content of the cyclic ether compound in the reaction liquid (liquid to be subjected to the photoreaction; also referred to as a reaction substrate solution) is preferably 1 to 50 mass%, more preferably 2 to 40 mass%, further preferably 4 to 35 mass%, even more preferably 6 to 30 mass%, still more preferably 10 to 25 mass%, still more preferably 12 to 23 mass%, and still more preferably 15 to 22 mass%.

[0020] [Photoreaction] In the present invention, the photoreaction is a reaction in which [1.1.1]propellane is reacted with a 1,2-diketone compound by irradiation with light to produce a 1,3-disubstituted BCP. The reaction scheme is as follows. R represents a hydrogen atom or a substituent.

[0021] [ka]

[0022] In the present invention, the photoreaction is carried out in a solvent containing an acyclic ether solvent having 5 or more carbon atoms, with the addition of a cyclic ether compound as a reaction promoter as described above. The photoreaction is preferably carried out by irradiating light having a wavelength of 300 to 500 nm, more preferably by irradiating light having a wavelength of 320 to 450 nm, and even more preferably by irradiating light having a wavelength of 340 to 430 nm. As the light source, a light-emitting diode (LED) lamp, an ultraviolet (UV) lamp, an incandescent lamp (e.g., a tungsten lamp), etc. can be used without any particular limitation. This photoreaction may be carried out as a batch reaction or a flow reaction, and is preferably carried out as a flow reaction from the viewpoint of light absorption efficiency.

[0023] The photoreaction in the flow reaction can be carried out using a photoreactor. The photoreactor can be constructed, for example, by wrapping a light-transmitting reaction tube around a light source cooling tube. A light source is disposed in the light source cooling tube, and is cooled by water or other solvent. It is also preferable to cover the photoreactor with a reflective material such as aluminum foil in order to suppress light loss. Examples of materials for the light-transmitting reaction tube include tetrafluoroethylene-hexafluoropropylene copolymer (FEP) tubes, tetrafluoroethylene-perfluoroalkylvinylether copolymer (PFA) tubes, polytetrafluoroethylene (PTFE) tubes, etc., but are not limited to these, and various materials can be used within the scope of the present invention without impairing the effects of the present invention.

[0024] The flow reaction can be carried out, for example, by preparing a solution in which [1.1.1]propellane, a 1,2-diketone compound, and a cyclic ether compound are present together in a solvent containing an acyclic ether solvent having 5 or more carbon atoms, and then pumping this solution into a reaction tube and allowing it to circulate within the reaction tube. Alternatively, a solution of [1.1.1]propellane dissolved in a solvent containing an acyclic ether solvent having 5 or more carbon atoms and a solution of a 1,2-diketone compound dissolved in a solvent containing an acyclic ether solvent having 5 or more carbon atoms can be circulated through different flow paths, and then these can be joined, and a photoreaction can be caused by a photoreactor while the joined liquid is flowing downstream. In this reaction, a cyclic ether compound, which is a reaction accelerator, is added at the latest before the photoreaction. For example, the cyclic ether compound can be included in a [1.1.1]propellane solution or a 1,2-diketone compound solution, or a liquid containing a cyclic ether can be joined before the photoreaction. Although the preferred reaction modes have been described above, the present invention is not limited to the above modes except as specified in the present invention. For example, application of a batch reaction is also a preferred embodiment of the present invention.

[0025] Next, preferred reaction conditions for the photoreaction will be described. The reaction temperature of the photoreaction can be, for example, -50 to 50°C. From the viewpoint of improving the yield, it is preferably -30 to 30°C, more preferably -20 to 20°C, and also preferably -10 to 10°C. The reaction time of the photoreaction is not particularly limited and can be set appropriately, for example, to 0.001 to 7000 minutes, or may be 0.01 to 5000 minutes, or may be 0.1 to 700 minutes.

[0026] In the above reaction, the reaction molar ratio of [1.1.1]propellane to the 1,2-diketone compound is appropriately adjusted in consideration of stoichiometry, etc. For example, [[1.1.1]propellane] / [1,2-diketone compound] can be 1 / 0.5 to 1 / 10, preferably 1 / 1 to 1 / 5, and more preferably 1 / 1 to 1 / 2.

[0027] The concentrations of [1.1.1]propellane and 1,2-diketone compound in the reaction solution (liquid to be subjected to photoreaction) are appropriately set according to the purpose and taking into consideration the above-mentioned reaction molar ratio. For example, the concentration of [1.1.1]propellane in the reaction solution can be 0.01 to 3 mol / L, and is also preferably 0.1 to 0.5 mol / L.

[0028] The yield in the production method of the present invention (the yield of 1,3-disubstituted BCP in the reaction of obtaining 1,3-disubstituted BCP by photoreacting [1.1.1]propellane with a 1,2-diketone compound, i.e., [molar amount of 1,3-disubstituted BCP produced] / [molar amount of [1.1.1]propellane as the starting material]) is preferably 80% or more, more preferably 85% or more, even more preferably 90% or more, and also preferably 92% or more. Such a high yield can be achieved by adding a cyclic ether compound as a reaction promoter.

[0029] In the production method of the present invention, the 1,3-disubstituted BCP produced by the photoreaction can be separated and purified. As the separation or purification method, a general method can be appropriately applied. For example, column chromatography, recrystallization, reprecipitation, sublimation, etc. can be applied alone or in combination.

[0030] The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. EXAMPLES

[0031] [Example 1] 1,3-Diacetyl BCP was obtained according to the following scheme.

[0032] [ka]

[0033] <Preparation of [1.1.1]propellane> 100 mL of cyclopentyl methyl ether (CPME) and 10 g of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane were placed in a 500 mL three-neck flask and cooled to -78°C under a nitrogen atmosphere. 42 mL of a solution of n-butyllithium dissolved in n-hexane at a concentration of 1.6 M was added thereto, and the mixture was stirred for 10 minutes to react. The mixture was then heated to 0°C and stirred for an additional 30 minutes. In this way, [1.1.1]propellane was obtained in the solvent. 30 mL of water was added thereto, and the mixture was heated to room temperature (25°C), and then separated to obtain an organic layer. The organic layer was cooled to 0°C, a distillation apparatus was connected, and the receiving flask was cooled to -78°C and distilled, and [1.1.1]propellane was transferred to the receiving flask. In this way, a CPME / n-hexane (3.6 / 1, mass ratio) solution containing [1.1.1]propellane at a concentration of 0.15 M was obtained. The yield of [1.1.1]propellane was 62%. The fact that [1.1.1]propellane was obtained was confirmed by the following data: 1 Chemical shift σ (ppm) by H-NMR (400 MHz, solvent: DMSO-d6, internal standard: tetramethylsilane (TMS)) = 2.04 (6H, s)

[0034] <Preparation of 1,3-diacetyl BCP> 1,3-Diacetyl BCP was prepared by a flow reaction. The flow reaction system used is as shown in FIG. 1. In this flow reaction system, a stainless steel (SUS316) tube 3 with an inner diameter of 1.0 mm and a length of 1.0 m was placed in a thermostatic bath 2 set at 0°C, and a PFA tube 4 with an inner diameter of 1.6 mm and a length of 3.0 m was connected downstream of the tube. This PFA tube 4 was wound around a light source cooling tube 5. A 385 nm LED (100 W) lamp was placed in the light source cooling tube 5 as a light source. The temperature of the light source cooling tube 5 (corresponding to the reaction temperature of the photoreaction) was set to 0°C. The reaction substrate solution 1 was delivered by a syringe pump.

[0035] The CPME / n-hexane solution containing 0.15M of [1.1.1]propellane obtained in the above <Preparation of [1.1.1]propellane> was mixed with 2.0 molar equivalents of 2,3-butanedione relative to [1.1.1]propellane (twice the molar amount of [1.1.1]propellane), and THF was added to the concentration shown in the table below and mixed. The mixture was cooled to 5°C and subjected to nitrogen bubbling for 5 minutes to obtain a reaction substrate solution (a reaction solution before being subjected to a photoreaction). This reaction substrate solution was sent into the flow path of the above flow reaction system at a flow rate of 1.2 mL / min, and 1,3-diacetyl BCP was produced by a photoreaction. The reaction time of this photoreaction (flow time in the PFA tube wrapped around the light source cooling tube 5) was 5 minutes. Using the resulting reaction solution, the yield of 1,3-diacetyl BCP from the photoreaction of [1.1.1]propellane with 2,3-butanedione was calculated by nuclear magnetic resonance spectroscopy (internal standard: biphenyl). The results are shown in the table below. The following data confirmed that 1,3-diacetyl BCP [alias: 1,1'-(bicyclo[1.1.1]pentane-1,3-diyl)bis(ethan-1-one)] was obtained. 1 H-NMR (400 MHz, solvent: DMSO-d6, internal standard: tetramethylsilane (TMS)) chemical shifts σ (ppm) = 2.16 (6H, s), 2.10 (6H, s).

[0036] [Examples 2 to 4] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0037] [Example 5] A MTBE / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was obtained in the same manner as in <Preparation of [1.1.1]propellane> in Example 1, except that the CPME used in <Preparation of [1.1.1]propellane> was changed to methyl tert-butyl ether (MTBE). Then, 1,3-diacetyl BCP was obtained in the same manner as in <Preparation of 1,3-diacetyl BCP> in Example 1, except that the MTBE / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was used instead of the CPME / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane with 2,3-butanedione is shown in the table below.

[0038] [Examples 6 to 8] 1,3-Diacetyl BCP was obtained in the same manner as in Example 5, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0039] [Example 9] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that 2-methyl THF was used instead of THF in Example 1. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0040] [Examples 10 to 12] 1,3-Diacetyl BCP was obtained in the same manner as in Example 9, except that the concentration of 2-methyl THF in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0041] [Example 13] 1,3-Diacetyl BCP was obtained in the same manner as in Example 9, except that a MTBE / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was used instead of a CPME / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M as in Example 5. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane with 2,3-butanedione is shown in the table below.

[0042] [Examples 14 to 16] 1,3-Diacetyl BCP was obtained in the same manner as in Example 13, except that the concentration of 2-methyl THF in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0043] [Example 17] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that a 405 nm LED (100 W) lamp was used as the light source in the light source cooling tube of the flow reaction system instead of a 385 nm LED (100 W) lamp. [1.1.1] The yield of 1,3-diacetyl BCP by the photoreaction of propellane and 2,3-butanedione is shown in the table below.

[0044] [Example 18] 1,3-Diacetyl BCP was obtained in the same manner as in Example 17, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0045] [Example 19] 1,3-Diacetyl BCP was obtained in the same manner as in Example 17, except that a MTBE / hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was used instead of a CPME / hexane solution containing [1.1.1]propellane at a concentration of 0.15 M as in Example 5. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane with 2,3-butanedione is shown in the table below.

[0046] [Example 20] 1,3-Diacetyl BCP was obtained in the same manner as in Example 19, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0047] [Example 21] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that an LED (100 W) lamp with a wavelength of 365 nm was used instead of an LED (100 W) lamp with a wavelength of 385 nm as the light source disposed in the light source cooling tube of the flow reaction system. [1.1.1] The yield of 1,3-diacetyl BCP by the photoreaction of propellane and 2,3-butanedione is shown in the table below.

[0048] [Example 22] 1,3-Diacetyl BCP was obtained in the same manner as in Example 21, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0049] [Example 23] 1,3-Diacetyl BCP was obtained in the same manner as in Example 21, except that a MTBE / hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was used instead of a CPME / hexane solution containing [1.1.1]propellane at a concentration of 0.15 M as in Example 5. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane with 2,3-butanedione is shown in the table below.

[0050] [Example 24] 1,3-Diacetyl BCP was obtained in the same manner as in Example 23, except that the THF concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0051] [Comparative Example 1] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that THF was not added to the reaction substrate solution in Example 1. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0052] [Comparative Example 2] 1,3-Diacetyl BCP was obtained in the same manner as in Example 5, except that THF was not added to the reaction substrate solution in Example 5. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0053] [Comparative Example 3] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that ethyl acetate (EtOAc) was used in place of THF in the reaction substrate solution. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0054] [Comparative Example 4] 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 3, except that the concentration of ethyl acetate in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0055] [Comparative Example 5] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that toluene was used in place of THF in the reaction substrate solution. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0056] [Comparative Example 6] 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 5, except that the toluene concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0057] [Comparative Example 7] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that acetonitrile was used in place of THF in the reaction substrate solution. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0058] [Comparative Example 8] 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 7, except that the acetonitrile concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0059] [Comparative Example 9] 1,3-Diacetyl BCP was obtained in the same manner as in Example 1, except that acetone was used in place of THF in the reaction substrate solution. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0060] [Comparative Example 10] 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 9, except that the acetone concentration in the reaction substrate solution was changed as shown in the table below. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0061] [Comparative Example 11] 1,3-Diacetyl BCP was obtained in the same manner as in Comparative Example 2, except that an LED (100 W) lamp with a wavelength of 405 nm was used as the light source in the light source cooling tube of the flow reaction system instead of the LED (100 W) lamp with a wavelength of 385 nm. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0062] [Comparative Example 12] 1,3-Diacetyl BCP was obtained in the same manner as in Comparative Example 2, except that an LED (100 W) lamp with a wavelength of 365 nm was used instead of an LED (100 W) lamp with a wavelength of 385 nm as the light source disposed in the light source cooling tube of the flow reaction system in Comparative Example 2. The yield of 1,3-diacetyl BCP by the photoreaction of [1.1.1]propellane and 2,3-butanedione is shown in the table below.

[0063] [Table 1]

[0064] As shown in the above table, it can be seen that when a tetrahydrofuran compound, which is a cyclic ether, is added to the reaction substrate solution, the yield is dramatically improved compared to when it is not added (Comparative Example 1 vs. Examples 1 to 4 and Examples 9 to 12, Comparative Example 2 vs. Examples 5 to 8 and Examples 13 to 16, Comparative Example 11 vs. Examples 19 and 20, Comparative Example 12 vs. Examples 23 and 24). Furthermore, when compounds other than cyclic ether compounds were used as the reaction accelerator, no effect of improving the yield was observed (Comparative Examples 3 to 10). These results show that cyclic ether compounds exhibit outstanding effects as reaction accelerators in the photoreaction of the present invention.

[0065] Although the present invention has been described in conjunction with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless specifically stated otherwise, and believe that the appended claims should be broadly construed without departing from the spirit and scope of the invention as set forth in the appended claims.

[0066] This application claims priority based on Patent Application No. 2021-148842, filed in Japan on September 13, 2021, the contents of which are incorporated herein by reference as part of the present specification. [Explanation of symbols]

[0067] 1. Reaction substrate solution (syringe pump) 2 Constant temperature bath 3. Stainless steel tube 4 PFA tubes 5 Light source cooling tube

Claims

1. A method for producing 1,3-disubstituted bicyclo[1.1.1]pentane, comprising: photoreacting reaction raw materials [1.1.1]propellane and a 1,2-diketone compound in a solvent containing an acyclic ether solvent having 5 or more carbon atoms to obtain 1,3-disubstituted bicyclo[1.1.1]pentane; and adding a cyclic ether compound to the reaction solution in addition to the solvent of the reaction raw materials.

2. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to claim 1, wherein the solvent for the reaction raw material does not contain a cyclic ether compound.

3. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to claim 1, wherein the acyclic ether solvent has 5 to 10 carbon atoms.

4. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to claim 1, wherein the acyclic ether solvent has 5 or 6 carbon atoms.

5. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 4, wherein the 1,2-diketone compound is a diacetyl compound or a glyoxylic acid compound.

6. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 4, wherein the cyclic ether compound is a tetrahydrofuran compound.

7. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 4, wherein the photoreaction is carried out by irradiation with light having a wavelength of 200 to 600 nm.

8. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 4, wherein the reaction temperature of the photoreaction is -50 to 50°C.

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