JP5322219B2 - Method for producing phosphole compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 3-oxo-&lambda;<SP>5</SP>-phosphole compound having various substituents. <P>SOLUTION: The method for producing the phosphole compound (1) represented by formula 1 [wherein, R<SP>1</SP>, R<SP>2</SP>and R<SP>5</SP>represent each a 6-12C aryl group or the like; R<SP>3</SP>and R<SP>4</SP>represent each an aryl group or the like; R<SP>6</SP>represents a 1-6C alkyl group; and Hal represents a halogen atom group] is provided. Otherwise, the phosphole compound (1) is produced by carrying out a cycloaddition reaction of compounds represented by formulas (15) and (16) [wherein, R<SP>11</SP>, R<SP>12</SP>and R<SP>15</SP>represent each H, a 6-12C aryl group or the like; R<SP>13</SP>and R<SP>14</SP>represent each an aryl group or the like; and X represents a leaving group]. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a method for producing a phosphole compound.

  Phosphor is a heterocyclic compound having a structure in which the nitrogen atom of pyrrole is replaced with phosphorus, but has a chemical property that is different from pyrrole, such as not having aromaticity.

  For example, as phosphole, 2H-phosphole and 3H-phosphole exist in the same manner as 2H-pyrrole and 3H-pyrrole, and a phosphorus atom may be in a pentavalent state such as phosphine oxide and sulfide. In this way, phosphole has isomers of various structures, so it cannot be said that the research has been sufficiently conducted.

  The initial studies on the synthesis and reactivity of these phosphole compounds are summarized in Non-Patent Document 1. Various uses and synthesis methods of π-conjugated compounds containing a phosphorus atom have been studied and are exemplified in Non-Patent Documents 2 to 3. Furthermore, Patent Document 1 demonstrates the properties of phosphole compounds as optical materials and metal ligands, and a method for producing the same has also been proposed. Patent Document 2 discloses a use as a polymer raw material and a production method thereof. In addition, Non-Patent Documents 4 to 5 describe the synthesis and physical properties of phosphole compounds with an expanded π-conjugated system, and Non-Patent Document 6 reports the synthesis and fluorescence characteristics of dendrimers having phosphole compounds as cores. ing.

The phosphole compound described in the above document is mainly λ ³ -1H-phosphole containing a trivalent phosphorus atom and an oxidant thereof such as oxide or sulfide. Although some reports have been made on the synthesis and reaction of 2H-phosphole, its physical properties are unknown.

The present inventors have so far studied phosphole compounds. For example, as shown in Non-Patent Documents 7 to 8, by reacting tert-butyldimethylsilyldiphenylphosphine or diphenylphosphine with dimethyl acetylenedicarboxylate, 3-oxo- having a pentavalent phosphorus atom and having a carbonyl group at the 3-position It has been reported that a phosphine digo derivative in which two λ ⁵ -phosphols are directly linked is obtained.

JP 2007-238570 A JP 2003-261585 A

F. Mathey, Accounts of Chemical Research (Acc. Chem. Res.), 37, 954 (2004) F. Mathey, Angewande Chemie International Edition (Angew. Chem. Int. Ed.), 42, 1578 (2003) T. Baumgartner, R.A. Reau, Chemical Reviews (Chem. Rev.), 106, 4681 (2006) T. Baumgartner et al., Chemistry-European Journal (Chem. Eur. J.), Vol. 11, p. 4687 (2005) H. -C. Su, R. Reau, et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), 128, 983 (2006) T. Sanji et al., Organic Letters (Org. Lett.), Vol. 9, p. 3611 (2007) Minoru Hayashi, Yasunobu Nishimura, Emi Morita, Yutaka Matsuura, Hiroshi Watanabe, Abstracts of the 86th Annual Meeting of the Chemical Society of Japan, 1J307 (2006) Minoru Hayashi, Yasunobu Nishimura, Emi Morita, Miho Okasaka, Keiko Kawaguchi, Yu Watanabe, Abstracts of the 87th Annual Meeting of the Chemical Society of Japan, 4E427 (2007)

  As described above, various phosphole compounds have been produced so far. However, there was no sufficiently simple and efficient production method.

  For example, all the methods for producing phosphole compounds disclosed in Patent Documents 1 and 2 are via a transition metal complex, but transition metal compounds are relatively expensive and cause environmental pollution. However, these methods are not suitable for large-scale synthesis.

In addition, as described in Non-Patent Documents 7 to 8, the present inventors synthesized a 3-oxo-λ ⁵ -phosphole compound from acetylenedicarboxylic acid diester and phosphines. However, according to this method, only phosphole having an alkoxycarbonyl group derived from acetylene dicarboxylic acid diester as a raw material can be synthesized on the phosphole ring. Nevertheless, there are no other reports on 3-oxo-λ ⁵ -phosphole compounds, and therefore no other synthetic methods are known.

Therefore, the problem to be solved by the present invention is to provide a method capable of easily and efficiently producing a 3-oxo-λ ⁵ -phosphole compound having various substituents and a novel phosphole compound.

The inventors of the present invention have made extensive studies to solve the above problems. As a result, if a phosphole ring is constructed from a λ ³ -phosphine compound having a specific structure and a halogen compound, a 3-oxo-λ ⁵ -phosphole compound having various substituents can be easily obtained without going through a transition metal complex. The present invention has been completed by finding that the present invention can be efficiently produced.

  The method for producing a phosphole compound represented by the formula (1) according to the present invention includes:

[Where:
R ¹ , R ² and R ⁵ are independently a hydrogen atom group, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, a substituent A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group which may have a substituent, and a heteroaryl group which may have a substituent _{Represents an} optionally substituted C _1-6 alkoxy group, amino group, cyano group, carboxy group, C _1-7 acyl group or C _2-7 alkoxycarbonyl group, or R ¹ and R ² May form a C _6-10 aryl group which may have a substituent together with a carbon atom to which each is bonded, or a heteroaryl group which may have a substituent,
R ³ and R ⁴ may independently have a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted heteroaryl group]
From the compound represented by Formula (2) and the compound represented by Formula (3),

［式中、Ｒ¹〜Ｒ⁵は上記と同義を示し、Ｒ⁶はＣ_1-6アルキル基を示し、Ｈａｌはハロゲン原子基を示す］
式（４）で表される化合物を得、

[Wherein, R ^{1 to} R ⁵ are as defined above, R ⁶ represents a C _1-6 alkyl group, and Hal represents a halogen atom group]
A compound represented by formula (4) is obtained,

［式中、Ｒ¹〜Ｒ⁶およびＨａｌは上記と同義を示す］
上記化合物（４）を環化反応に付すことを特徴とする。

[Wherein R ^{1 to} R ⁶ and Hal are as defined above]
The compound (4) is subjected to a cyclization reaction.

  In the method of the present invention, there are a mode in which the cyclization reaction is performed under basic conditions, a mode in which heating is performed, and a mode in which heating is performed under reduced pressure.

Furthermore, the present inventors can construct 3-oxo-λ ⁵ having various substituents without going through a transition metal complex if a phosphole ring is constructed from a λ ³ -phosphine compound having a specific structure and an acetylene compound. -The present invention was completed by solving the above problems by finding that a phosphole compound can be easily and efficiently produced.

  The method for producing a phosphole compound represented by the formula (11) according to the present invention includes:

[Where:
R ¹¹ , R ¹² and R ¹⁵ are each independently a hydrogen atom group, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group which may have a substituent, and a heteroaryl group which may have a substituent , An optionally substituted C _1-6 alkoxy group, amino group, cyano group, carboxy group, C _1-7 acyl group or C _2-7 alkoxycarbonyl group,
R ¹³ and R ¹⁴ may independently have a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted heteroaryl group]
The compound represented by the formula (15) and the compound represented by the formula (16) are subjected to a cycloaddition reaction.

［式中、Ｒ¹¹〜Ｒ¹⁵は上記と同義を示し、Ｘは脱離基を示す］

[Wherein, R ^{11 to} R ¹⁵ are as defined above, and X represents a leaving group]

In the present invention, the “leaving group” refers to a group that can be easily removed in the cycloaddition reaction. Examples thereof include a halogen atom group, a C _1-6 alkoxy group, and —OCO—C _1-6 alkyl group.

In the above method, the substituent for the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group or C _1-6 alkoxy group includes a C _6-10 aryl group, a heteroaryl group, C _{1 -6} alkoxy group, amino group, cyano group, hydroxyl group, carboxy group, and one or more selected from the group consisting of halogen atom groups can be mentioned as substituents for C _6-10 aryl group or heteroaryl group Is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, heteroaryl group, C _1-6 alkoxy group, amino group, cyano group, hydroxyl group, carboxy And one or more selected from the group consisting of a group, a halogen atom group, a C _1-7 acyl group and a C _2-7 alkoxycarbonyl group.

In the present invention, the “C _1-6 alkyl group” refers to a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned. Of these, C _1-4 alkyl is preferable, and C _1-2 alkyl is more preferable.

The “C _2-6 alkenyl group” refers to a linear or branched aliphatic hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 6 carbon atoms. For example, vinyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, pentenyl, hexenyl and the like. Preferred is C _2-5 alkenyl, more preferred is C _2-4 alkenyl, and most preferred is 2-propenyl (allyl).

The “C _2-6 alkynyl group” refers to a linear or branched aliphatic hydrocarbon group having one or more triple bonds between carbon atoms and having 2 to 6 carbon atoms. For example, ethynyl, 1-methylethynyl, 1-propynyl, 2-propynyl, 1-methyl-1-propynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, pentynyl, hexynyl and the like. C _2-5 alkynyl is preferable, and C _2-4 alkynyl is more preferable.

The “C _3-10 cycloalkyl group” refers to a cyclic aliphatic hydrocarbon group having 3 to 10 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like can be mentioned. Of these, C _3-6 cycloalkyl is preferred.

The “C _6-10 aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. For example, phenyl, naphthyl, indenyl, etc., preferably phenyl.

  The “heteroaryl group” refers to a 5-membered aromatic heterocyclyl group, a 6-membered aromatic heterocyclyl group or a condensed ring aromatic heterocyclyl group having at least one heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom. For example, 5-membered ring heteroaryl groups such as pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole; 6-membered heteroaryl groups such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl; indolyl, isoindolyl, Mention may be made of condensed ring aromatic heterocyclyl groups such as quinolinyl, isoquinolinyl, benzofuranyl, isobenzofuranyl, chromenyl and the like. Preferred is heteroaryl containing a nitrogen atom, and more preferred is pyridinyl.

The “C _1-6 alkoxy group” refers to a linear or branched aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexoxy, etc., preferably C _1-4 alkoxy, more preferably C _{1- 2} alkoxy.

The "amino group", in addition to the unsubstituted amino group, substituted in one of the aforementioned C _1-6 mono C _1-6 alkylamino group and two of the C _1-6 alkyl group substituted in the alkyl group Di-C _1-6 alkylamino group is included. Examples of the amino group include amino; mono C _1- such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, t-butylamino, n-pentylamino, n-hexylamino and the like. ₆ alkylamino; dimethylamino, diethylamino, di (n-propyl) amino, diisopropylamino, di (n-butyl) amino, diisobutylamino, di (n-pentyl) amino, di (n-hexyl) amino, ethylmethylamino And diC _1-6 alkylamino such as methyl (n-propyl) amino, n-butylmethylamino, ethyl (n-propyl) amino, n-butylethylamino, and the like. An unsubstituted amino group is preferable.

  Examples of the “halogen atom group” include a fluoro group, a chloro group, a bromo group, and an iodo group, preferably a chloro group or a bromo group, and more preferably a chloro group.

The “C _1-7 acyl group” refers to the remaining atomic group obtained by removing OH from an aliphatic carboxylic acid having 1 to 7 carbon atoms. For example, formyl, acetyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, etc., preferably C _1-4 acyl A group, more preferably acetyl.

“C _2-7 alkoxycarbonyl group” refers to a group in which the C _1-6 alkoxy group is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, n-hexoxycarbonyl and the like. The group is preferably a (C _2-6 alkoxy) carbonyl group, and more preferably a (C _3-5 alkoxy) carbonyl group.

  When an aryl group, heteroaryl group, or the like has a substituent, the number of substituents may be 2 or more as long as substitution is possible. When there are a plurality of substituents, they may be the same as or different from each other.

  Compound (1) and compound (11) may be in the form of a solvate such as a hydrate, and these are included in the scope of the present invention.

  Compound (1) and compound (11) may be salts, and these are included in the scope of the present invention. Suitable salts of compound (1) and compound (11) include, for example, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate Organic acid salts such as: inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; amino acid salts such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; calcium Examples thereof include alkaline earth metal salts such as salts and magnesium salts.

According to the method of the present invention, 3-oxo-λ ⁵ -phosphole compounds having various substituents can be easily and efficiently produced without going through a transition metal complex.

  The phosphole compound (1) of the present invention is produced by the following scheme.

  Hereinafter, the first production method of the phosphole compound according to the present invention will be described in the order of execution.

Process A
Step A is a step of synthesizing the phosphonium salt (4) from the phosphine compound (2) and the halogen compound (3).

The phosphine compound (2) can be synthesized by a known method. For example, R.M. K. Dieter et al. Org. Chem. 67, p.847- (2002) and S. Ma et al. Org. Chem. , 57, p. 709 (1992), after adding HI to the substituted propiolate, E. Tunney, J.A. Org. Chem. , 52, p.748 (1987), by carrying out an iodine-phosphorus exchange reaction using silylphosphine and a palladium catalyst. In addition, with respect to the phosphine compound (2) in which R ¹ and R ² each form an aryl group together with adjacent carbon atoms, an orthoiodinated benzoic acid ester compound produced by a commercially available or known synthesis method is used as a raw material. . E. Tunney, J.A. Org. Chem. , 52, p. 748 (1987). A. Krasovskiy, Chem. Int. Ed. , 43, p.3333 (2004) using an ortho-halogenated benzoic acid compound and an organometallic compound obtained from organolithium or organomagnesium by a halogen-metal exchange reaction, and producing by a phosphorous-carbon bond forming reaction. it can.

  The halogen compound (3) may be purchased as long as it is commercially available, but may be produced from a commercially available compound by a general method since it has a relatively simple structure.

In addition, when R ¹ , R ² or R ⁵ is an amino group having no substituent or when an active substituent such as a carboxy group is present on the aryl group, these active groups are temporarily protected. In addition, the reaction may proceed to remove the protecting group as needed.

  The reaction conditions in Step A are not particularly limited. For example, the halogen compound (3) may be added to the solution of the phosphine compound (2) and stirred. The reaction is preferably carried out under a nitrogen stream. Moreover, it is also possible to react without adding a solvent, such as using a halogen compound (3) as a solvent.

  The solvent used in Step A is not particularly limited as long as it can appropriately dissolve compound (2) and compound (3) and does not inhibit the reaction. For example, aromatic hydrocarbons such as benzene and toluene; It can be selected from nitriles such as acetonitrile and chloroacetonitrile; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethylacetamide.

  The temperature during this reaction depends on the starting materials and the solvent, but can be about room temperature to 110 ° C. In addition, the process A and the process B can also be performed continuously by raising the said temperature. This point will be described later.

  The reaction time after the addition depends on the starting materials and the solvent, but is usually about 1 to 24 hours. The completion of the reaction may be confirmed by TLC or the like.

  Since the reaction of Step A proceeds very easily and hardly produces by-products, the phosphonium salt (4) can be obtained almost quantitatively by simply distilling off the solvent after the reaction. Alternatively, Step B can be carried out in the solution state without distilling off the solvent. That is, the scope of the present invention includes an embodiment in which the next step is performed without isolating the phosphonium salt.

Process B
Step B is a step of synthesizing the phosphole compound (1) according to the present invention by subjecting the phosphonium salt (4) to a cyclization reaction. Such cyclization reactions include those carried out under basic conditions, those carried out by heating, and those carried out by heating under reduced pressure. Hereinafter, these reaction conditions will be described.

· Cyclization reaction phosphonium salt under basic conditions (4), when R ⁵ is generated by an electron withdrawing group stable phosphorus ylide, such as cyano group, by the liquid of the solution with basic Easily cyclizes. Specifically, the basic compound may be added little by little after dissolving the phosphonium salt (4) in water.

  A water-miscible organic solvent such as methanol or ethanol may be added to the aqueous solution of the phosphonium salt (4) in order to enhance the solubility.

  The basic compound is not particularly limited as long as it exhibits solubility in the solvent used, and for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can be used. These basic compounds are preferably added as an aqueous solution of about 1 to 4N in order to suppress rapid progress of the reaction.

  Confirmation of when the reaction mixture becomes basic can also be performed with a pH meter or the like, but it is easy to add a pH indicator such as phenolphthalein to the reaction mixture and color it. is there. Specifically, a small amount of phenolphthalein is added to the aqueous solution of the phosphonium salt (4), and then the aqueous solution of the basic compound is added little by little, followed by repeated stirring, and the reaction mixture turns red. At this point, the reaction can be terminated.

  After completion of the reaction, the target compound phosphole compound (1) can be purified by a general method. For example, the reaction mixture is extracted with an organic solvent immiscible with water, such as ethyl acetate or chloroform, and the organic solvent layer is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate and then concentrated under reduced pressure. Furthermore, you may refine | purify by methods, such as column chromatography and recrystallization, as needed.

  In addition to the above method, as in the conditions of the Wittig reaction, strong compounds such as butyl lithium, lithium diisopropylamide (LDA), and potassium hexamethyldisilazide (KHMDS) are added to the phosphonium salt (4) in an appropriate solvent such as THF. It is also possible to carry out intramolecular cyclization by preparing phosphorus ylide by the action of a base; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride. Usually, the preparation and cyclization reaction of phosphorus ylide are carried out at a low temperature. However, when the cyclization reaction is slow, the cyclization can be promoted by heating.

-Cyclization reaction by heating The phosphonium salt (4) is easily cyclized to form the phosphole compound (1) even by simple heating.

  For example, the reaction temperature in Step A is about 80 to 150 ° C., and the synthesis of the phosphonium salt (4) and the cyclization reaction can be carried out continuously. The reaction time in this case may be determined by preliminary experiments, confirmation of consumption of raw material compounds, or the like, but can usually be about 6 to 48 hours.

  After completion of the reaction, it may be purified by a usual method. For example, the phosphole compound (1) can be obtained by concentrating the reaction mixture under reduced pressure and purifying the residue by silica gel column chromatography or recrystallization.

-Cyclization reaction by heating under reduced pressure The phosphonium salt (4) can be more efficiently cyclized not only by heating but also by heating under reduced pressure.

  For example, the phosphonium compound (1) can be obtained by thoroughly drying the phosphonium salt (4) obtained in the step A and then heating at about 100 to 200 ° C. with reduced pressure. The reaction time in this case may be determined by preliminary experiments, confirmation of consumption of raw material compounds, or the like, but can usually be about 1 to 12 hours. In this case, depending on the structure of the raw material compound, the reaction at a temperature of about 150 ° C. or lower may produce a by-product having no phosphole structure. In this case, the side reaction is suppressed by performing the reaction at a higher temperature. be able to.

  After completion of the reaction, it may be purified by a usual method. For example, the phosphole compound (1) can be obtained by cooling the reaction product to room temperature and then purifying it by silica gel column chromatography or recrystallization.

  The phosphole compound (11) of the present invention can be produced by the following scheme.

  Hereafter, the 2nd manufacturing method of the phosphole compound based on this invention is demonstrated.

  Step C is a step of synthesizing the phosphole compound (11) by reacting the phosphine compound (15) with the acetylene compound (16).

The phosphine compound (15) can be easily synthesized by a known method. For example, when a phosphine compound (15) in which X is a C _1-6 alkoxy group is required, R ¹⁵ may be introduced into the α-position of the phosphinoacetate compound by an α-position substitution reaction known to those skilled in the art. A phosphine compound (15) in which X is a C _1-6 alkoxy group is obtained by subjecting a phosphine compound having a methyl group substituted by R ¹⁵ or a borane complex thereof to an α-position substitution reaction known to those skilled in the art. It can also be synthesized by introducing an alkoxycarbonyl group into the methyl group. Furthermore, the phosphine compound (15) can also be synthesized by substituting the halogen group of the phosphinoacetate compound in which a halogen group is introduced at the α-position with the desired R ¹⁵ by a nucleophilic substitution reaction known to those skilled in the art. Can do.

  The phosphine compound (15) as a raw material may be easily oxidatively decomposed in air. In that case, the phosphine compound (15) may be derived into the borane complex represented by the formula (17) and decomposed back to the phosphine compound (15) when the phosphole compound (11) is synthesized. .

  In the case of decomposing the borane complex (17), a highly nucleophilic amine may be allowed to act in a solvent.

  The solvent used in the decomposition reaction of the borane complex (17) is not particularly limited as long as it can dissolve the borane complex (17) appropriately and does not inhibit the reaction, but examples thereof include dimethylformamide and dimethylacetamide. Amides; nitriles such as acetonitrile, propionitrile, benzonitrile; aromatic hydrocarbons such as benzene and toluene can be selected.

  Examples of highly nucleophilic amines include cyclic amines such as 1,4-diazabicyclo [2.2.2] octane (DABCO), morpholine, quinuclidine, and N, N, N ′, N ′,-tetramethylethylenediamine. (TMEDA) or the like can be used.

  The concentration of the borane complex (17) in the decomposition reaction of the borane complex (17) may be adjusted as appropriate, but is usually about 0.1 mg / mL or more and 1 mg / mL or less. The amount of amine used may be the same or substantially the same as that of the borane complex (17). At the time of reaction, in order to suppress oxidative decomposition of the produced phosphine compound (15), it is preferable to replace the inside of the system with an inert gas such as argon gas or nitrogen gas.

  The temperature and time for the decomposition reaction of the borane complex (17) may be adjusted as appropriate, but can usually be about 1 hour or more and 10 hours or less at room temperature.

  After completion of the reaction, the produced phosphine compound (15) may be isolated and purified, but the decomposition reaction of the borane complex (17) generally proceeds quantitatively, and the phosphine compound (15) Since it may be oxidatively decomposed when brought into contact with air, it is preferable to proceed to the next step as it is.

  The step C may be performed by adding the acetylene compound (16) to the solution of the phosphine compound (15) and stirring with heating. When the borane complex (17) is decomposed into the phosphine compound (15), the acetylene compound (16) may be added to the reaction solution.

  Since the acetylene compound (16) has a relatively simple structure, it can be purchased if there is a commercially available product, and if there is no commercially available product, it can be produced from a commercially available compound by methods known to those skilled in the art. Can do.

  Although the usage-amount of an acetylene compound (16) should just be adjusted suitably, what is necessary is just to make it the same or substantially the same molar amount as a phosphine compound (15). Generally, the one that can be obtained inexpensively or the one that can be easily manufactured is used in excess.

  Although the solvent used in Step C is not particularly limited, the solvents mentioned as those that can be used in the decomposition reaction of the borane complex (17) can be used. That is, amides such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile, propionitrile, and benzonitrile; aromatic hydrocarbons such as benzene and toluene can be used.

  The reaction temperature in step C may be adjusted as appropriate, but can usually be about room temperature to about 120 degrees. Although the reaction time may be adjusted as appropriate, it can usually be about 5 hours or more and 20 hours or less. The completion of the reaction may be confirmed by TLC or the like.

  After completion of the reaction, it may be purified by a usual method. For example, since the target phosphole compound (11) can be said to have a relatively high lipid solubility, the reaction solution is extracted with chloroform or ethyl acetate, washed and dried, and purified by silica gel column chromatography or recrystallization. That's fine.

  Depending on the reaction temperature of step C and the raw material compound, a phosphole reductant represented by formula (18) may be obtained. In that case, the phosphole compound (11) can be easily obtained by oxidizing the phosphole reductant (18) with an oxidizing agent.

  The solvent used in this reaction is not particularly limited as long as it can appropriately dissolve the phosphor reductant (18) and does not inhibit the reaction. For example, halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, etc. Hydrocarbons and the like can be used.

  As an oxidizing agent that can be used in this reaction, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), chloranil, or the like can be used. If it is desired to oxidize substituents in parallel, a strong oxidizing agent may be used, but generally DDQ or the like is preferably used.

  The concentration of the reduced phosphole (18) in this reaction may be adjusted as appropriate, but it can usually be about 10 mg / mL or more and 30 mg / mL or less. The amount of the oxidizing agent may be appropriately adjusted according to the type of the oxidizing agent to be used, etc., but is usually about 1.0 mol times or more and 5.0 mol times or less with respect to the phosphor reductant (18). be able to.

  The temperature of this reaction may be appropriately adjusted according to the type of oxidizing agent, but can usually be room temperature. The reaction time may be adjusted as appropriate, but can usually be about 30 minutes or more and 10 hours or less. The completion of the reaction may be confirmed by TLC or the like.

  After completion of the reaction, it may be purified by a usual method. For example, after the solvent is distilled off under reduced pressure, it may be purified by silica gel column chromatography, recrystallization, or the like. If necessary, the oxidizing agent may be decomposed.

  Further, if necessary, a functional group conversion reaction may be performed on the substituent. Such a reaction can be carried out by methods known to those skilled in the art.

  The phosphole compound produced by the method of the present invention is conjugated at least with a phosphorus-carbon double bond and an oxo group. Depending on the substituents at other positions, conjugation may be more sophisticated. Therefore, it is considered that the phosphole compound of the present invention can be used as an excellent electron transporting material or light emitting material. For example, there is a possibility that a thin film made of the phosphole compound of the present invention is formed by a vacuum deposition method or the like, and this can be used as an organic EL light emitting layer. Moreover, since the phosphole compound which concerns on this invention shows the outstanding fluorescence, it can also be used as a pigment | dye.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

  Example 1 Synthesis Method of Novel Phosphor Compound A-Cyclization of Phosphonium Salt under Basic Conditions

Methyl o-diphenylphosphinobenzoate (200 mg, 0.63 mmol) was dissolved in benzene (0.5 mL). Under a nitrogen stream, ethyl bromoacetate (108 mg, 0.64 mmol) was added to the solution, and the mixture was stirred at 55 ° C. for 1 hour. Subsequently, the phosphonium salt was quantitatively obtained by distilling off the solvent. The analysis results of the phosphonium salt by NMR are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.06 (t, 3H, J = 7.2 Hz, CH ₃ ), 3.74 (s, 3H, OCH ₃ ), 4.00 (q, 2H, J = 7.2 Hz, O- _{CH 2), 5.28 (d,} 2H, J = 16Hz, P-CH 2), 7.54-8.42 (m, 14H, aromatic H);
³¹ P-NMR (162 MHz, CDCl ₃ ) δ27.4

The phosphonium salt was dissolved in water (50 mL). Two drops of a 2% phenolphthalein methanol solution were added to the solution, and 2N aqueous sodium hydroxide solution was added dropwise with vigorous stirring until a slight red color remained. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated to give 2-ethoxycarbonyl-P, P-diphenylbenzo-3-oxo-λ ⁵ -phosphole as a white solid. The yield was 152 mg and the yield was 66%. The analysis results and fluorescence characteristics of the compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.18 (t, 3H, J = 7.2 Hz, CH ₃ ), 4.16 (q, 2H, J = 7.2 Hz, CH ₂ ), 7.45-8.12 (m, 14H, aromatic H);
³¹ P-NMR (162 MHz, CDCl ₃ ) δ 20.4;
FABMAS 375 [M + H] ⁺ ;
R = 0.20 (CHCl ₃ / AcOEt = 3/1)
λem = 450.5nm

  Example 2 Synthesis Method of Novel Phosphor Compound B-Cyclization of Phosphonium Salt by Heating

Methyl o-diphenylphosphinobenzoate (104 mg, 0.33 mmol) was dissolved in chloroacetonitrile (0.4 mL) and stirred at 120 ° C. for 2 hours under a nitrogen stream. Next, the solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixed solvent of chloroform / ethyl acetate = 3/1 as an eluent to give 2-cyano-P, P-diphenylbenzo-3 which was a white solid. -Oxo-λ ⁵ -phosphole was obtained. The yield was 106 mg, and the yield was 100%. The analysis results and fluorescence characteristics of the compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.50-8.15 (m, 14H, aromatic H);
³¹ P-NMR (162 MHz, CDCl ₃ ) δ 18.5;
FABMAS 328 [M + H] ⁺ ;
R = 0.70 (AcOEt)
λem = 464.5nm

  Example 3 Synthesis Method of Novel Phosphor Compound C-Cyclization of Phosphonium Salt by Heating under reduced pressure

Methyl o-diphenylphosphinobenzoate (121 mg, 0.38 mmol) was dissolved in toluene (2.0 mL). Benzyl bromide (0.1 mL, 0.84 mmol) was added to the solution and stirred at room temperature for 2 days. Subsequently, the phosphonium salt was quantitatively obtained by distilling off the solvent. The analysis results of the phosphonium salt by NMR are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.67 (s, 3H, OCH ₃ ), 5.28 (d, 2H, P-CH ₂ ), 6.90-8.40 (m, 19H, aromatic H);
³¹ P-NMR (162 MHz, CDCl ₃ ) δ27.2

The phosphonium salt was dried under reduced pressure at 50 ° C. for 1 hour, then heated while being reduced in pressure, and heated at 150 ° C. for 5 hours. Next, after cooling, the reaction mixture is purified by silica gel column chromatography using ethyl acetate as an eluent to give 2-phenyl-P, P-diphenylbenzo-3-oxo-λ ⁵ -phosphole, which is an amorphous solid. Obtained. The yield was 3.3 mg, and the yield was 15%. The analysis results of the compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ6.83-8.18 (m, 19H, aromatic H);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 73.7 (d, J = 115 Hz), 122.4 (s), 122.9 (d, J = 85 Hz), 123.6 (d, J = 12 Hz), 124.4 (d, J = 9Hz), 125.7 (d, J = 89Hz), 126.9 (d, J = 7Hz), 128.1 (s), 129.5 (d, J = 13Hz), 129.8 (d, J = 11Hz), 133.2 (d, J = 11Hz), 133.3 (d, J = 3Hz), 133.6 (d, J = 2Hz), 136.9 (d, J = 13Hz), 147.0 (d, J = 14Hz), 178.3 (d, J = 33Hz);
³¹ P-NMR (162 MHz, CDCl ₃ ) δ 17.6;
R = 0.65 (AcOEt)

Example 4 Synthesis Method of Novel Phosphor Compound C—Cyclization of Phosphonium Salt by Heating under reduced pressure In Example 3 above, except that the conditions for vacuum heating of the phosphonium salt were set at 190 ° C. for 4.5 hours, The compound was obtained in a yield of about 80%. However, since the target compound contained a small amount of impurities, further purification conditions are under investigation.

  Example 5 Synthesis Method of Novel Phosphor Compound B-Cyclization of Phosphonium Salt by Heating

Methyl (Z) -3-diphenylphosphinocinnamate (112 mg, 0.31 mmol) was dissolved in chloroacetonitrile (0.4 mL) and stirred at 120 ° C. for 18 hours under a nitrogen stream. Next, the solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixed solvent of chloroform / ethyl acetate = 3/1 as an eluent to give 2-cyano-5-phenyl-P, a yellow amorphous solid. , P-diphenyl-3-oxo-λ ⁵ -phosphole was obtained. The yield was 81 mg and the yield was 74%. The analysis results of the compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17-7.79 (m, 16H);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 46.8 (d, J = 137.5 Hz), 117.2 (d, J = 17.5 Hz), 120.2 (d, J = 87.6 Hz), 127.1 (d, J = 5.9 Hz) ), 129.5 (s), 130.1 (d, J = 13.1Hz), 130.6 (s), 130.8 (d, J = 8.5Hz), 133.0 (d, J = 11.1Hz), 134.5 (d, J = 3.1Hz) ), 136.6 (d, J = 73Hz), 145.4 (d, J = 9.2Hz), 183.7 (d, J = 34.5Hz);
R = 0.25 (CHCl ₃ / AcOEt = 3/1)

  Example 6 Synthesis Method of Novel Phosphor Compound A-Cyclization of Phosphonium Salt under Basic Conditions

  A toluene solution (0.5 mL) of methyl o-diphenylphosphinobenzoate (50 mg, 0.16 mmol) was added to a reactor filled with nitrogen, and benzyl bromide (30 mg, 0.17 mmol) was further added. For 3 hours. Then the solvent was distilled off. The residue was dried at 50 ° C. under reduced pressure, and THF (2.0 mL) was added to form a suspension. Lithium hydride (3.7 mg, 0.46 mmol) was added to the suspension and stirred at 50 ° C. for 19 hours. Thereafter, water was added to stop the reaction. The reaction mixture was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (yield: 74%).

  Example 7 Synthesis Method of Novel Phosphor Compound A-Cyclization of Phosphonium Salt under Basic Conditions

  A reactor filled with nitrogen was charged with a prenyl bromide solution (0.2 mL) of methyl o-diphenylphosphinobenzoate (50 mg, 0.16 mmol) and stirred at room temperature for 7 hours. Then the solvent was distilled off. The residue was dried at 50 ° C. under reduced pressure, and THF (2.0 mL) was added to form a suspension. Lithium hydride (3.7 mg, 0.46 mmol) was added to the suspension and stirred at room temperature for 8 hours. Thereafter, water was added to stop the reaction. The reaction mixture was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 1/1) to obtain the target compound as a yellow amorphous substance (yield: 30 mg, yield: 54%).

  Reference Example 1 Functional group conversion of a new phosphole compound

  A bromo compound was synthesized by the same method as in Example 2 above. A bromo compound (100 mg, 0.25 mol) was placed in a reactor filled with argon. Separately, palladium acetate (27 mg) and triphenylphosphine (12 mg) were dissolved in dry DMF (1 mL) in a vial to prepare a catalyst solution. After the catalyst solution was added to the reactor, styrene (35 μL, 0.30 mmol) and sodium acetate (32 mg, 0.37 mmol) were added and heated at 140 ° C. for 5.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 8/1) to obtain the pale yellow target compound (yield: 62%).

  Reference Example 2 Functional group conversion of a new phosphole compound

  A bromo compound was synthesized by the same method as in Example 2 above. To a reactor filled with argon, bromo compound (100 mg, 0.25 mol), phenylboronic acid (45 mg, 0.36 mmol), sodium carbonate (78 mg, 3.0 eq.), Palladium acetate (5.37 mg, 10 mol%) , Triphenylphosphine (13 mg, 20 mol%) and dry DMF (1 mL) were added and heated at 100 ° C. for 3.5 hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 8/1) to obtain a light yellow target compound (yield: 92%).

  Example 8 Production of a novel phosphole compound by the second production method according to the present invention

  A DMF solution (1 mL) of methyl diphenylphosphinophenylacetate-borane complex (49.5 mg, 0.14 mmol) was placed in a reactor filled with argon, and DABCO (15.9 mg, 0.14 mmol) was further added at room temperature. Stir for 2.5 hours. Subsequently, 4-phenyl-3-butyn-2-one (26.5 mg, 0.18 mmol) was added, and the mixture was heated with stirring at 100 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform and washed once with 1N hydrochloric acid, water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 9/1) to obtain the target compound as a red amorphous substance (yield: 45.6 mg, yield: 72%).

  Example 9 Production of a novel phosphole compound by the second production method according to the present invention

  A reactor filled with argon was charged with an acetonitrile solution (1 mL) of methyl diphenylphosphinophenylacetate-borane complex (50.0 mg, 0.14 mmol), and DABCO (16.1 mg, 0.14 mmol) was further added at room temperature. Stir for 2.5 hours. Then, 4- (2-thienyl) -3-butyn-2-one (23.7 mg, 0.16 mmol) was added and stirred with heating at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform and washed once with 1N hydrochloric acid, water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) to obtain the target compound as a red amorphous substance (yield: 51.9 mg, yield: 80%). ).

Example 10 Production of a novel phosphole compound by the second production method according to the present invention (1) Production of phosphole reductant

  A toluene solution (2 mL) of methyl diphenylphosphinophenylacetate-borane complex (99.3 mg, 0.29 mmol) was placed in a reactor filled with argon, and DABCO (32.0 mg, 0.29 mmol) was further added at room temperature. Stir for 2.5 hours. Subsequently, dimethyl acetylenedicarboxylate (44.6 mg, 0.31 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform and washed once with 1N hydrochloric acid, water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 8/1) to obtain a phosphor reduced product which was a yellow amorphous substance (yield: 64 mg, yield: 50%).

  (2) Production of phosphole compounds

DDQ (1.7 mg, 0.074 mmol) was added to a dichloromethane solution (1.5 ml) of the phosphor reduced product (30.0 mg, 0.067 mmol) obtained in the above reaction, and the mixture was stirred at room temperature for 1 hour. When the reaction solution was analyzed by ¹ H-NMR and ³¹ P-NMR, it was revealed that a sufficiently pure phosphole compound was quantitatively obtained.

  Hereinafter, the results of producing phosphole compounds in the same manner as in the above Examples or Reference Examples are summarized in Tables 1 to 5. In the table, the first method according to the present invention for carrying out the cyclization reaction under basic conditions with sodium hydroxide in the same manner as in Example 1 was A1; The first method according to the present invention for carrying out the cyclization reaction is A2; the first method according to the present invention for carrying out the cyclization reaction by heating in the same manner as in Example 2 above; B; Let C be the first method according to the invention for carrying out the reaction. However, in Example 35, KHMDS was used instead of lithium hydride as the base.

As described above, according to the method of the present invention, 3-oxo-λ ⁵ -phosphole compounds having various substituents can be produced very simply and efficiently.

Claims (9)

A method for producing a phosphole compound represented by the formula (1):

[Where:
R ¹ , R ² and R ⁵ are independently a hydrogen atom group, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, a substituent A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group which may have a substituent, and a heteroaryl group which may have a substituent _{Represents an} optionally substituted C _1-6 alkoxy group, amino group, cyano group, carboxy group, C _1-7 acyl group or C _2-7 alkoxycarbonyl group, or R ¹ and R ² May form a C _6-10 aryl group which may have a substituent together with a carbon atom to which each is bonded, or a heteroaryl group which may have a substituent,
R ³ and R ⁴ may independently have a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted heteroaryl group]
From the compound represented by Formula (2) and the compound represented by Formula (3),

[Wherein, R ^{1 to} R ⁵ are as defined above, R ⁶ represents a C _1-6 alkyl group, and Hal represents a halogen atom group]
A compound represented by formula (4) is obtained,

[Wherein R ^{1 to} R ⁶ and Hal are as defined above]
A method comprising subjecting the compound (4) to a cyclization reaction.   The method according to claim 1, wherein the cyclization reaction is performed under basic conditions.   The method according to claim 1, wherein the cyclization reaction is performed by heating.   The method according to claim 1, wherein the cyclization reaction is performed by heating under reduced pressure. A substituent of a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-6 alkoxy group, a C _6-10 aryl group, a heteroaryl group, a C _1-6 alkoxy group, The method according to any one of claims 1 to 4, wherein the number is one or more selected from the group consisting of an amino group, a cyano group, a hydroxyl group, a carboxy group, and a halogen atom group. The substituent of the C _6-10 aryl group or heteroaryl group is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, heteroaryl group, C _{1- 6.} One or more selected from the group consisting of ₆ alkoxy groups, amino groups, cyano groups, hydroxyl groups, carboxy groups, halogen atom groups, C _1-7 acyl groups and C _2-7 alkoxycarbonyl groups. 6. The method according to any one of 5. A method for producing a phosphole compound represented by formula (11), comprising:

[Where:
R ¹¹ , R ¹² and R ¹⁵ are each independently a hydrogen atom group, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group which may have a substituent, and a heteroaryl group which may have a substituent , An optionally substituted C _1-6 alkoxy group, amino group, cyano group, carboxy group, C _1-7 acyl group or C _2-7 alkoxycarbonyl group,
R ¹³ and R ¹⁴ may independently have a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a substituent. A C _2-6 alkynyl group, a C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted heteroaryl group]
A method comprising subjecting a compound represented by the formula (15) and a compound represented by the formula (16) to a cycloaddition reaction.

[Wherein, R ^{11 to} R ¹⁵ are as defined above, and X represents a leaving group] A substituent of a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-6 alkoxy group, a C _6-10 aryl group, a heteroaryl group, a C _1-6 alkoxy group, The method according to claim 7, wherein the number is one or more selected from the group consisting of an amino group, a cyano group, a hydroxyl group, a carboxy group, and a halogen atom group. The substituent of the C _6-10 aryl group or heteroaryl group is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, heteroaryl group, C _{1- 6} or 1 or 2 selected from the group consisting of ₆ alkoxy groups, amino groups, cyano groups, hydroxyl groups, carboxy groups, halogen atom groups, C _1-7 acyl groups and C _2-7 alkoxycarbonyl groups 9. The method according to 8.