Method for producing alkene derivatives

Abstract

To provide a method of making alkene derivatives that are economically useful.SOLUTION: The method of making alkene derivatives comprises (a) a step of obtaining an alkene derivative by the action of a solvated electron on a compound represented by formula (1) in the figure (in formula (1), the wavy lines represent the bond positions of substituents, R0 is, e.g., a substituent shown in parentheses in the formula, and R1 and R2 are each an optional substituent, excluding the case where R2 is a "hydrogen atom" or a "substituent for which the bond in O-R2 is cleaved by the action of a solvated electron").SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an alkene derivative. [Background technology]

[0002] Alkene derivatives are used for various purposes, such as raw materials for medicines, agricultural chemicals, fragrance compounds, industrial materials, etc., or as intermediates for these. Various synthesis methods are known for alkene derivatives, for example, they can be obtained by the Wittig reaction, which converts the C=O double bond of a carbonyl compound into a C=C double bond. However, the control of the cis-trans isomers of alkene derivatives by the Wittig reaction is not perfect. Therefore, when it is desired to control the cis-trans isomers more precisely when synthesizing alkene derivatives, it is usually necessary to convert propyne to the following formula (91):

[0003] [ka]

[0004] In one embodiment, an alkene derivative is obtained by a reaction represented by the formula (91): (wherein R is an optional substituent).

[0005] The advantage of producing an alkene derivative by such a reaction is that the carbanion of propyne is easily produced, and carbon can be easily increased by a nucleophilic substitution reaction with a haloalkane derivative (the reaction shown as "coupling" in formula (91)), and the subsequent alkyne derivative can be (a) catalytically hydrogenated with a Lindlar catalyst to produce a cis (Z) alkene derivative, and (b) Birch reduction to produce a trans (E) alkene derivative, each of which is more selective than the Wittig reaction. The above formula (91) shows the case of (b) Birch reduction as an example. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Birch, A. J., J. Chem. Soc. 1944, 430. Summary of the Invention [Problem to be solved by the invention]

[0007] However, the inventors have found that propyne, which is the starting material for the synthesis method represented by formula (91), is a very expensive reagent (approximately 2 million yen per kg) and is therefore not economically useful.

[0008] In view of the above, an object of the present invention is to provide an economically useful method for producing an alkene derivative. [Means for solving the problem]

[0009] As a result of intensive research, the inventors of the present invention have surprisingly discovered a new reaction in which an alkene derivative is produced in one step by reacting solvated electrons with a 2-propyn-1-ol derivative. Since 2-propyn-1-ol (propargyl alcohol) is cheaper than propyne (approximately 10,000 yen per kg), this reaction makes it possible to produce an alkene derivative at a lower cost than conventional methods.

[0010] Thus, a brief outline of representative inventions among those disclosed in this application is as follows.

[0011] [1] (a) Formula (1):

[0012] [ka]

[0013] (In formula (1), the wavy lines indicate the bonding positions of the substituents, and R 0 is any of the substituents shown in parentheses in the formula, and R 1 , R 2 , R 3 and R 4 are each an optional substituent, and R 5is a linear or branched alkylene group which may have any substituent. 2 is "hydrogen atom" or "solvated electron" 2 or R 3 and R 4 At least one of the following is "hydrogen atom" or "solvated electron" 3 Between or 4 The bond between the substituents is broken.) is reacted with solvated electrons to form a compound represented by the following formula (2):

[0014] [ka]

[0015] (In formula (2), R 1a is R in the above formula (1). 1 If there is no part in it that reacts with the solvated electron, R 1 is the same substituent as R 1 If there is a moiety in the compound that reacts with the solvated electron, the moiety is a substituent after the reaction.

[0016] [2] In the method for producing an alkene derivative according to [1], prior to the step (a), (b) Formula (3):

[0017] [ka]

[0018] The hydroxy group of the compound represented by the formula 2 (R 2 is R in the above formula (1). 2 ) and is protected by the following formula (4):

[0019] [ka]

[0020] (In formula (4), R 2 is R in the above formula (1). 2 and after the step (b), (c) A compound represented by the formula (4) and the following formula (5):

[0021] [ka]

[0022] (In formula (5), X is any halogen atom, and R 1 is R in the above formula (1). 1 is the same substituent as that of the compound represented by the formula (1),

[0023] [ka]

[0024] (In formula (1a), R 1 and R 2 is R in the above formula (1). 1 and R 2 and obtaining a compound represented by the formula:

[0025] [3] In the method for producing an alkene derivative according to [2], R 2 is a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group, a tert-butyldimethylsilyl group, an ethoxyethyl group, a benzoyl group or an acetyl group.

[0026] [4] In the method for producing an alkene derivative according to [2], R 2 is a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group, a tert-butyldimethylsilyl group or an ethoxyethyl group.

[0027] [5] In the method for producing an alkene derivative according to any one of [1] to [4], R 1 is expressed by the following formula (6):

[0028] [ka]

[0029] (In formula (6), the wavy line indicates the bonding position of the substituent, and n is an integer of 1 or more.) A method for producing an alkene derivative.

[0030] [6] In the method for producing an alkene derivative according to [5], the compound represented by formula (1) is represented by the following formula (1b):

[0031] [ka]

[0032] (In formula (1b), R 2 is R in the above formula (1). 2 and n is the same as in formula (6), and in the step (a), a compound represented by the following formula (2b):

[0033] [ka]

[0034] (wherein n is the same value as in the formula (1b)), after the step (a), (d) reacting the compound represented by formula (2b) with an acid to obtain a compound represented by the following formula (7):

[0035] [ka]

[0036] (wherein n is the same value as in formula (2b)) to obtain a compound represented by formula (7).

[0037] [7] The method for producing an alkene derivative according to [6], wherein n in the formula (1b) is 4, and in the step (d), (E)-6-octenal is obtained as the compound represented by the formula (7).

[0038] [8] In the method for producing an alkene derivative according to [6], after the step (d), (e) reacting a Wittig reagent having an aldehyde group with the compound represented by formula (7) to obtain a compound represented by the following formula (8):

[0039] [ka]

[0040] (wherein n is the same value as in formula (7)) to obtain a compound represented by formula (8).

[0041] [9] The method for producing an alkene derivative according to [8], wherein n in the formula (1b) is 2, and in the step (e), (2E,6E)-2,6-octadienal is obtained as the compound represented by the formula (8). Effect of the Invention

[0042] According to the present invention, an economically useful method for producing an alkene derivative can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Hereinafter, an embodiment of the present invention will be described in detail. In this specification, the symbol "to" means a range including a lower limit and an upper limit.

[0044] (Production method of alkene derivatives (1)) Hereinafter, a method for producing an alkene derivative according to one embodiment of the present invention (hereinafter, sometimes referred to as "the present production method (1)") will be described in detail. Note that, unless otherwise specified, matters mentioned in the present production method (1) also apply to the present production method (2), the present octenal production method, and the present octadienal production method described later.

[0045] The present production method (1) comprises: (a) reacting a compound represented by the following formula (1):

[0046] [ka]

[0047] (In formula (1), the wavy lines indicate the bonding positions of the substituents, and R 0 is any of the substituents shown in parentheses in the formula, and R 1 , R 2 , R 3 and R 4 are each an optional substituent, and R 5 is an optionally substituted alkylene group, provided that R 2 is "hydrogen atom" or "solvated electron" 2 or R 3 and R 4 At least one of the following is "hydrogen atom" or "solvated electron" 3 Between or 4 The bond between the substituents is broken.) is reacted with solvated electrons to form a compound represented by the following formula (2):

[0048] [ka]

[0049] (In formula (2), R 1a is R in the above formula (1). 1 If there is no part in it that reacts with the solvated electron, R 1 is the same substituent as R 1If there is a moiety in the compound that reacts with the solvated electrons, the moiety is a substituent after the reaction.

[0050] The above step (a) can be summarized as the following reaction formula (10):

[0051] [ka]

[0052] (In formula (10), R 1 , R 2 and R 1a has the same definition as in formula (1) and formula (2).) or the reaction represented by the following formula (10a):

[0053] [ka]

[0054] (In formula (10a), R 1 , R 3 , R 4 and R 1a has the same definition as in formula (1) and formula (2).) or the reaction represented by the following formula (10b):

[0055] [ka]

[0056] (In formula (10b), R 1 , R 5 and R 1a has the same definition as equation (1) and equation (2).

[0057] That is, the present production method (1) is a method for obtaining a compound represented by formula (2) (alkene derivative) from a compound represented by formula (1) in one step (the reaction represented by formula (10), formula (10a) or formula (10b)), and as a result, the alkene derivative can be produced economically.

[0058] The inventors have now completed the present invention by discovering that the compound of formula (1) is represented by the following formula (1a):

[0059] [ka]

[0060] (In formula (1a), R 1 and R 2 is R in the above formula (1). 1 and R 2 Based on the common general technical knowledge at the time of filing the present application, a compound represented by the following formula (92):

[0061] [ka]

[0062] (In formula (92), R 1 is an optional substituent, R 2a is "hydrogen atom" or "solvated electron" 2a When a compound represented by the formula (93):

[0063] [ka]

[0064] (In formula (93), R 1a is R in the above formula (92) 1 or R 1 If there is a portion in the solvated electron that reacts with the solvated electron, it will be the substituent after the reaction.) is thought to be the main compound that will be produced (this will be called "Prediction 1").

[0065] In addition, the following formula (94):

[0066] [ka]

[0067] (In formula (94), R 1 and R 2 are each optional substituents, where R 2 is "hydrogen atom" or "solvated electron" 2 When a compound represented by the formula (95): (which is the same as the compound represented by the formula (1a) above but with the numbers changed for convenience) is subjected to a reduction reaction with solvated electrons, a compound represented by the formula (95):

[0068] [ka]

[0069] (In formula (95), R 2 is R in the above formula (94) 2 is the same as R 1a is R in the above formula (94) 1 or R 1 If there is a portion in the solvated electron that reacts with the solvated electron, it will be the substituent after the reaction.) is thought to be the main compound that will be produced (this will be called "Prediction 2").

[0070] As a result of the inventors' investigation of the above, the conclusion was that Prediction 1 was correct, but Prediction 2 was incorrect. First, regarding Prediction 1, among the compounds represented by formula (92), for example, R 2a When R is a benzyl group or a p-methoxybenzyl group, the solvated electrons not only reduce the carbon-carbon triple bond, but also cleave (cleave) the bond between the carbon atom at the benzyl position and the oxygen atom, ultimately adding a proton to the anionized oxygen atom to form a hydroxy group, which explains the result. This is why, in general, when a benzyl group is used as a protecting group for a hydroxy group, the Birch reduction is used to remove the benzyl group. 2aWhen R is a hydrogen atom (i.e., when a hydroxyl group is bonded to the carbon atom at the propargyl position), the solvated electrons do not affect the hydroxyl group, and only the reduction of the carbon-carbon triple bond occurs (R 1 If there is a part in the solvated electron that reacts with the solvated electron, the reaction will 1a It goes without saying that this is the case.

[0071] On the other hand, prediction 2 is -OR bonded to the propargyl carbon atom. 2 does not change, and only the reduction of the carbon-carbon triple bond occurs (R 1 If there is a part in the solvated electron that reacts with the solvated electron, the reaction will 1a However, contrary to expectation 2, the following formula (1a):

[0072] [ka]

[0073] (In formula (1a), R 1 and R 2 are each optional substituents, where R 2 is "hydrogen atom" or "solvated electron" 2 When a solvated electron acts on a compound represented by the formula (94) (which is the same as the compound represented by the formula (94) above, but the numbers are changed for convenience), a compound represented by the formula (2):

[0074] [ka]

[0075] (In formula (2), R 1a is R in the above formula (1a) 1 or R 1 If there is a part in the solvated electron that reacts with the solvated electron, it is the substituent after the reaction.) was found to be the main compound produced. 2 (R2 is "hydrogen atom" or "solvated electron" 2 The inventors have been investigating the detailed reaction mechanism, but have not found that the elimination reaction of -OR occurs on the carbon atom at the propargyl position. 2 It has been confirmed that, as far as the present inventors can verify, the reaction is highly reproducible for the compound represented by the formula (1) that satisfies the condition that the compound is bonded to the compound, including the examples described below. In addition, the present production method (1) can selectively obtain an alkene derivative in the trans form (E form) in the same manner as the normal Birch reduction, and is also advantageous in this respect.

[0076] Based on the above findings, the present inventors have completed the invention relating to the present production method (1). According to the present production method (1), an alkene derivative can be obtained from a 2-propyn-1-ol derivative in one step and in a high yield comparable to or higher than that of the conventional method. In particular, according to the present production method (1), a trans-form (E-form) alkene derivative can be obtained with very high selectivity.

[0077] Here, the compound represented by the above formula (1), which is the starting material of the present production method (1), will be described. As described above, the important point of the present production method (1) is that "-OR bonded to the carbon atom at the propargyl position by a solvated electron" is r (r is an integer for convenience in distinguishing the substituents, R r is "hydrogen atom" or "solvated electron" r The reason is that an elimination reaction of "a substituent in which the bond between the substituent and the substituent is broken" occurs. The same applies below.

[0078] Therefore, as an example of the reaction included in the step (a) of the present production method (1), first, in the compound represented by the above formula (1) which is the starting material, -OR is added to the carbon atom at the propargyl position. r The following formula (10) when one bond is present:

[0079] [ka]

[0080] (In formula (10), R 1 , R 2 and R 1a has the same definition as in formula (1) and formula (2). ) is an example of such a reaction. An example of such a reaction is when the starting material is a protected hydroxyl group bonded to the carbon atom at the propargyl position.

[0081] Next, another example of the reaction included in the step (a) of the present production method (1) is a reaction in which -OR is added to the carbon atom at the propargyl position of the compound represented by the formula (1) as the starting material. r The following formula (10a) shows the case where two are bonded:

[0082] [ka]

[0083] (In formula (10a), R 1 , R 3 , R 4 and R 1a has the same definition as in formula (1) and formula (2). ) is an example of such a reaction. An example of such a reaction is when the carbon atom at the propargyl position is a carbon atom that constitutes an aldehyde group, and the aldehyde group is acetal-protected and used as the starting material.

[0084] Similarly, another example of the reaction included in the step (a) of the present production method (1) is a reaction in which -OR is added to the carbon atom at the propargyl position of the compound represented by the formula (1) as the starting material. 5 When bonded to O- in a ring (formally -OR r The same as when two are bonded.)

[0085] [ka]

[0086] (In formula (10b), R 1 , R 5 and R 1a has the same definition as in formula (1) and formula (2). ) is included. An example of such a reaction is when the carbon atom at the propargyl position is a carbon atom that constitutes an aldehyde group, and the aldehyde group is reacted with a diol to protect it as a cyclic acetal, which is used as the starting material. Note that R 5 R is a linear or branched alkylene group which may have any substituent, but the number of carbon atoms of the alkylene group is not limited. 5 Specific examples of the above include a methylene group, an ethylene group, and a propylene group. Formally, a 1,3-dioxetan-2-yl group, a 1,3-dioxolan-2-yl group, and a 1,3-dioxan-2-yl group are directly bonded to the triple-bonded carbon atom.

[0087] In step (a) of the present production method (1), -OR is attached to the carbon atom at the propargyl position. r There are three (-OR 2 , -OR 3 AND -OR 4 ) is bonded to the following formula (10c):

[0088] [ka]

[0089] (In formula (10c), R 1 , R 2 , R 3 and R 4 are each optional substituents, where R 2 , R 3 and R 4 At least one of the following is "hydrogen atom" or "solvated electron" r The reaction represented by the formula (I) is also possible.

[0090] In step (a) of the present production method (1), a carbon atom at the propargyl position is provided with -OR 4a (R 4a is "hydrogen atom" or "solvated electron" 4a The bond between the -OR group is broken. 3 (R 3 is "hydrogen atom" or "solvated electron" 3 The substituent is not one of "a substituent that breaks the bond between the ring and the ring" and "a substituent that breaks the bond between the ring and the ring".

[0091] [ka]

[0092] (In formula (10i), R 1 , R 3 and R 1a is defined as the same as in formula (1) and formula (2), and R in formula (10i) 4a is "hydrogen atom" or "solvated electron" 4a R is a substituent that breaks the bond between 3 is "hydrogen atom" or "solvated electron" 3 The reaction represented by the formula (I) is also possible.

[0093] In addition, the present inventors have discovered that in step (a) of the present production method (1), a starting material having the following formula (96):

[0094] [ka]

[0095] (In formula (96), R 1 and R 2 is R in the above formula (1). 1 and R 2and m is an integer of 2 or more or 0. In the compound represented by the formula (97), the solvated electrons simply reduce the carbon-carbon triple bond, in accordance with Prediction 2.

[0096] [ka]

[0097] (In formula (97), R 2 is R in the above formula (96) 2 and m is the same as m in formula (96). 1a is R in the above formula (96) 1 or R 1 If there is a portion in the solvated electron that reacts with the solvated electron, it will be the substituent after the reaction.) It has been confirmed that the compound represented by

[0098] In step (a) of the present production method (1), the origin of the "solvated electron" is not particularly limited, but examples thereof include solvated electrons generated under Birch reduction conditions (i.e., electrons generated by dissolving a metal in liquid ammonia and solvating the generated electrons in ammonia), solvated electrons generated under Benkesser reduction conditions using a lower alkylamine such as methylamine, ethylamine, or ethylenediamine instead of liquid ammonia, solvated electrons generated in a system by mixing a metallic sodium dispersion (metallic sodium dispersed in mineral oil as fine particles of 5 to 10 μm) and a crown ether in tetrahydrofuran without using liquid ammonia or a lower alkylamine (hereinafter these may be collectively referred to as "liquid ammonia, etc."), and solvated electrons released from a visible light redox catalyst activated by light irradiation, and preferred examples thereof include solvated electrons generated under Birch reduction conditions. In addition, in step (a) of the present production method (1), electrons can also be supplied directly from an electrode in an electrochemical reaction that can be substituted for Birch reduction, such as a Birch reduction-type electrolysis reaction in which cathode reduction is performed in liquid ammonia, a Birch reduction-type electrolysis reaction using a magnesium electrode in the presence of lithium perchlorate (LiClO4), or a Birch reduction-type electrolysis reaction in which tris(pyrrolidino)phosphoramide and 1,3-dimethylurea are added as additives in the presence of a lithium salt.

[0099] In the step (a) of the present production method (1), when solvated electrons generated under Birch reduction conditions or solvated electrons generated under Benkesser reduction conditions (hereinafter collectively referred to as "Birch reduction, etc.") are employed, the metal to be used may be lithium, sodium, potassium, calcium, etc., and lithium is preferred. The amount of the metal to be used is not particularly limited, but is preferably 1.0 to 20.0 mol, and more preferably an excess of 2.0 to 10.0 mol, per mol of the compound represented by the formula (1) (hereinafter sometimes referred to as "reaction substrate"), from the viewpoint of smooth progress of the reaction.

[0100] In addition, when Birch reduction or the like is employed in step (a) of the present production method (1), it is preferable to add a solvent (additive solvent) that does not react with solvated electrons to liquid ammonia (or lower alkylamine) as appropriate in order to sufficiently dissolve (including "disperse"; the same applies below) the reaction substrate in liquid ammonia or the like and smoothly proceed with the reaction. Examples of the additive solvent used in this case include diethyl ether, tetrahydrofuran, diisopropyl ether, and tert-butyl methyl ether. The amount of the additive solvent is determined based on the solubility of the reaction substrate and economical efficiency, and is usually 1.0 to 50 parts by volume, and preferably 3.0 to 10 parts by volume, per part by mass of the reaction substrate. When Birch reduction or the like is employed in step (a) of the present production method (1), the order of addition of the reaction substrate, metal, liquid ammonia, etc. is not particularly limited. For example, there may be mentioned a method in which the reaction substrate is dissolved in an additive solvent, and then liquid ammonia or the like is added, and then the metal is added to generate solvated electrons, or a method in which the metal is added to liquid ammonia or the like to generate solvated electrons, and then the reaction substrate dissolved in an additive solvent is added.

[0101] In addition, when Birch reduction or the like is employed in step (a) of the present production method (1), a protonating agent such as ammonium chloride, alcohol, or water may be added as in the case of a normal Birch reduction, but the present inventors have confirmed that the presence or absence of a protonating agent does not affect the progress of step (a). When liquid ammonia is used, the reaction temperature in step (a) of the present production method (1) is preferably −100 to −33° C., particularly −80 to −33° C., with the boiling point of ammonia being the upper limit. The reaction time varies depending on reaction conditions such as the reaction substrate and temperature, but the reaction is completed in about 1 or 2 minutes to 30 minutes, or at most 30 hours.

[0102] In the present production method (1), R 1 is arbitrary and is not particularly limited, but as shown in the "Production method of (E)-6-octenal" and "Production method of (2E,6E)-2,6-octadienal" described later, R 1 is expressed by the following formula (6):

[0103] [ka]

[0104] (in formula (6), the wavy line indicates the bonding position of the substituent, and n is an integer of 1 or more) (that is, a (1,3-dioxolan-2-yl)alkyl group) is preferable.

[0105] Hereinafter, in this manufacturing method (1), R 1 The effect of the substituent represented by formula (6) will be described. Since the substituent represented by formula (6) does not react with solvated electrons, the following formula (1b):

[0106] [ka]

[0107] (In formula (1b), R 2 is R in the above formula (1). 2 and n are defined the same as n in the above formula (6). The compound represented by the following formula (2b):

[0108] [ka]

[0109] (In formula (2b), n is the same value as n in formula (1b).) This is expressed by the following reaction formula (10-1):

[0110] [ka]

[0111] (In formula (10-1), R 2 and n are defined the same as in formula (1b).

[0112] Since the 1,3-dioxolan-2-yl group is a protecting group for an aldehyde group (acetal protection), the compound represented by formula (2b) can be represented by the following formula (11):

[0113] [ka]

[0114] (In formula (11), n ​​is the same value as n in formula (10-1)) (hereinafter, sometimes referred to as "step (d)"), the compound can be easily converted to a compound having an aldehyde group at the terminal by deprotection using an acid. 1 When is a substituent represented by formula (6), a trans-form (E-form) alkene derivative having an aldehyde group at its terminal (hereinafter sometimes referred to as "(E)-alkenal") can be easily and selectively obtained from a 2-propyn-1-ol derivative. Note that an example of obtaining an (E)-alkenal via step (d) after step (a) of the present production method (1) will be described in detail later in "Production method of (E)-6-octenal".

[0115] In addition, (E)-alkenals are very useful because the aldehyde group can be converted to a carboxyl group by oxidation, the aldehyde group can be converted to a hydroxyl group by reduction, or the aldehyde group can be converted to an alkene by a Wittig reaction.

[0116] [ka]

[0117] (In formula (12), n is the same value as n in formula (11).) A reaction represented by this formula (12) (hereinafter sometimes referred to as "step (e)") can be used to obtain an (E,E)-alkadienal as an alkene derivative. In step (e), a Wittig reagent having an aldehyde group is reacted with an (E)-alkenal, and since the Wittig reagent becomes a stable ylide due to the aldehyde group, the main product of the compound produced is an alkene in a trans form (E form). As a result, by passing through step (d) and then step (e), an (E,E)-alkadienal can be easily and selectively obtained. An example of obtaining an (E,E)-alkadienal by passing through step (d) and then step (e) after step (a) of the present production method (1) will be described in detail below as "a method for producing (2E,6E)-2,6-octadienal".

[0118] In the present production method (1), R 1 When contains a moiety that reacts with solvated electrons, that moiety also reacts during the above step (a), which will be described in detail below.

[0119] First, the compound represented by formula (1) is represented by the following formula (1c):

[0120] [ka]

[0121] (In formula (1c), R 2 is R in the above formula (1). 2 is the same substituent as R 6 is an optional substituent, where R 6 is "hydrogen atom" or "solvated electron" 6 In the case of a compound represented by the formula (1), that is, the compound represented by the formula (1) is a substituent in which the bond between R 1 -CH2OR 6 The following will be described by taking the case where:

[0122] In this case, -OR is attached to the propargyl carbon atom. 2 AND -OR 6According to the present production method (1), the solvated electrons form -OR 2 AND -OR 6 Both of the following formula (2c):

[0123] [ka]

[0124] (E)-2-butene represented by the formula (2) 1a The main product is aryl methyl groups.

[0125] Next, R in the formula (1) 1 When R contains a functional group that can be reduced by solvated electrons, it is reduced as known to those skilled in the art. 1 If the -OR has a benzene ring, a partial reduction reaction of the benzene ring occurs. If the -OR has an alkyne, a reduction reaction to an (E)-alkene occurs. If the -OR has a bond between the carbon atom at the benzylic position and a heteroatom such as a nitrogen atom, oxygen atom, sulfur atom, or halogen atom, a reduction reaction accompanied by the cleavage of the bond occurs. If the -OR has an aldehyde group or a ketone group, a reduction reaction to an alcohol occurs. 2 This occurs simultaneously with the elimination reaction of

[0126] As a more specific example, the compound represented by formula (1) is, for example, the compound represented by the following formula (1d):

[0127] [ka]

[0128] (In formula (1d), R 2 is R in the above formula (1). 2 is the same substituent as R 7 is the action of any "solvated electron" 7 In the case of a compound represented by the formula (1), that is, R 1-CH2OR 7 The following will be described by taking the case where:

[0129] In this case, -OR is attached to the propargyl carbon atom. 2 AND -OR 7 and are bonded together, but R 7 is converted to OR by the action of solvated electrons. 7 Since the bond between -OR is broken by the solvated electrons, the present production method (1) can be used to break the bond between -OR 2 While R 7 is replaced with a hydrogen atom, and the resulting compound has the following formula (2d):

[0130] [ka]

[0131] (E)-2-buten-1-ol represented by the formula (2) 1a The main product is -CH2OH.

[0132] As described above, in the present production method (1), R 1 In either case, R in formula (1) contains a moiety that reacts with the solvated electron. 1 -OR is attached to the propargyl carbon atom 2 Since it does not inhibit the elimination reaction of R 1 may be any substituent without any problem.

[0133] In the present production method (1), R 2 , R 3 and R 4 (hereinafter collectively referred to as "R r ") is sometimes called "hydrogen atom" or "solvated electron by the action of OR r R in formula (1) is optional, but is generally usable as a protecting group and highly versatile, except for "a substituent that breaks the bond between R and R" 2 , R 3 and R 4are preferably any one of a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group, a tert-butyldimethylsilyl group, an ethoxyethyl group, a benzoyl group and an acetyl group.

[0134] In addition, since liquid ammonia or the like is used under conditions such as the Birch reduction, basic substances are generated in addition to solvated electrons in the system. Therefore, when step (a) is performed under conditions such as the Birch reduction, R in formula (1) 2 , R 3 and R 4 are preferably either 2-tetrahydropyranyl, methyl, methoxymethyl, tert-butyldimethylsilyl or ethoxyethyl. These substituents do not react with either solvated electrons or bases, and therefore the elimination reaction in step (a) proceeds easily, increasing the yield of the compound represented by formula (2) (the desired alkene derivative) as shown in the examples below. On the other hand, R in formula (1) 2 , R 3 and R 4 are benzoyl or acetyl groups, the elimination reaction in step (a) proceeds to give a compound represented by formula (2) (the desired alkene derivative). However, these substituents are replaced by hydrogen atoms (deprotected) by a base, not by the action of solvated electrons, and therefore, as shown in the examples described later, R 2 , R 3 and R 4 is a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group, a tert-butyldimethylsilyl group, or an ethoxyethyl group. However, in the step (a) of the present production method (1), if solvated electrons are generated under conditions that do not use liquid ammonia or the like, no basic substances are generated in the system, and therefore, R 2 , R 3 and R 4 are benzoyl or acetyl groups, the elimination reaction in step (a) also proceeds, and the compound represented by formula (2) (the desired alkene derivative) is obtained by reacting with R 2 , R 3 and R 4is either a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group, a tert-butyldimethylsilyl group, or an ethoxyethyl group, respectively.

[0135] In the present production method (1), R 2 , R 3 and R 4 The solvated electrons are removed from the r Examples of the substituent that "cleaves the bond between the hydroxyl group and ... r The "substituent whose bond between the oxygen atom and the solvated electron is cleaved" is essentially synonymous with the "substituent whose bond between the oxygen atom and the solvated electron is cleaved" because a proton is added to the oxygen atom that finally becomes an anion in step (a) to become --OH.

[0136] In the present production method (1), R 1 Specific examples of include a hydrogen atom, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, an aromatic heterocyclic group, a halogen atom, an alkoxy group, a cycloalkoxy group, an aryloxy group, an aralkyloxy group, an alicyclic heterocyclic oxy group, an aromatic heterocyclic oxy group, an alkylthio group, a cycloalkylthio group, an arylthio group, an aralkylthio group, an alicyclic heterocyclic thio group, an aromatic heterocyclic thio group, an alkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, an alicyclic heterocyclic amino group, an aromatic heterocyclic amino group, or a silyl group. 1 In terms of design, it is preferable that the -OR be one that does not react with solvated electrons. However, as mentioned above, even if it reacts with solvated electrons, it is not necessary to use -OR bonded to the carbon atom at the propargyl position. 2 , -OR 3AND / OR -OR 4 It does not inhibit the elimination reaction of the cation.

[0137] The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. There is no particular restriction on the chain length. The aliphatic hydrocarbon group may have a substituent, and there is no particular restriction on the type, number, or position of the substituent. Specific examples of the aliphatic hydrocarbon group include, but are not limited to, alkyl and alkenyl groups having 1 to 20 carbon atoms.

[0138] The alicyclic hydrocarbon group may be saturated or unsaturated between the ring-constituting atoms, and the number of ring members is not particularly limited. In addition to a single ring, it may also include a ring assembly such as a condensed ring or a spiro ring. The alicyclic hydrocarbon group may have a substituent, and the number and the position of the substituent are not particularly limited. Examples of the alicyclic hydrocarbon group include, but are not limited to, a cycloalkyl group having 3 to 10 carbon atoms, and preferably a cycloalkenyl group having 4 to 10 carbon atoms.

[0139] The alicyclic heterocyclic group is a non-aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. It includes not only single rings but also ring assemblies such as condensed rings and spiro rings. The bond between the ring-constituting atoms may be saturated or unsaturated, and there is no particular restriction on the number of ring members. There is no restriction on the type, number, and position of the heteroatom. Preferred examples of heteroatoms include oxygen atoms, nitrogen atoms, and sulfur atoms. Examples of the heteroatom include alicyclic heterocyclic groups having preferably 2 to 7 carbon atoms, particularly preferably 2 to 5 carbon atoms, and preferably 1 to 5 heteroatoms, particularly preferably 1 to 3 carbon atoms. When the heteroatom has more than one heteroatom, the heteroatoms may be the same or different types of atoms. Examples of the alicyclic heterocyclic group include, but are not limited to, a nitrogen-containing alicyclic heterocyclic group such as a monocyclic four-membered azetidinyl group, a five-membered pyrrolidinyl group, a six-membered piperidyl group, a piperazinyl group, etc., a monocyclic three-membered oxiranyl group, a four-membered oxetanyl group, a five-membered tetrahydrofuryl group, a six-membered 2-tetrahydropyranyl group, etc., a sulfur-containing alicyclic heterocyclic group such as a monocyclic five-membered tetrahydrothiophenyl group, a nitrogen-containing oxygen-containing alicyclic heterocyclic group such as a monocyclic six-membered morpholinyl group, etc., a nitrogen-containing sulfur-containing alicyclic heterocyclic group such as a monocyclic six-membered thiomorpholinyl group, etc., etc., but are not limited thereto. In addition, the alicyclic heterocycle may have a substituent, and there is no particular restriction on the number and the position of the substituent.

[0140] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0141] The alkoxy group is preferably an alkoxy group having 1 to 10 carbon atoms, and specific examples thereof include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, etc. The cycloalkoxy group is preferably a cycloalkoxy group having 3 to 10 carbon atoms, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0142] The alkylthio group is preferably an alkylthio group having 1 to 20 carbon atoms, and examples thereof include, but are not limited to, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group. The cycloalkylthio group is preferably a cycloalkylthio group having 3 to 10 carbon atoms, and specific examples thereof include, but are not limited to, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, and a cyclohexylthio group. The alicyclic heterocyclic thio group includes the alicyclic heterocyclic groups shown above as the heterocyclic moiety. These may further have a substituent. The substituent may be one or more, and when the group has more than one substituent, the substituents may be the same or different from each other. There is also no particular limitation on the position of the substituent. The substituent may be the same as those exemplified as the substituent of the aliphatic hydrocarbon group.

[0143] (Production method of alkene derivatives (2)) In another embodiment of the present invention, a method for producing an alkene derivative (hereinafter sometimes referred to as "the present production method (2)") comprises the steps of: (b) Formula (3):

[0144] [ka]

[0145] The hydroxy group of the compound represented by the formula (2-propyn-1-ol, propargyl alcohol) is protected by a protecting group R 2 (R 2 is R in the above formula (1). 2 ) and is protected by the following formula (4):

[0146] [ka]

[0147] (In formula (4), R 2 is R in the above formula (1). 2and after the step (b), (c) A compound represented by the formula (4) and the following formula (5):

[0148] [ka]

[0149] (In formula (5), X is any halogen atom, and R 1 is R in the above formula (1). 1 (which is the same as the above.) to obtain a compound represented by formula (1). That is, the present production method (2) is a method for producing an alkene derivative using 2-propyn-1-ol (propargyl alcohol) as a raw material, which is carried out in the order of steps (b), (c), and (a).

[0150] The step (b) can be summarized by the following reaction formula (13):

[0151] [ka]

[0152] (In formula (13), R 2 has the same definition as equation (3).

[0153] The step (c) can be summarized as the following reaction formula (14):

[0154] [ka]

[0155] (In formula (14), X, R 1 and R 2 has the same definition as equations (4) and (5).

[0156] Step (c) will be described in more detail. A specific embodiment of the reaction represented by the above formula (14) is represented by the following formula (14-1):

[0157] [ka]

[0158] (In formula (14-1), base represents a base, and X and R 1 and R 2 has the same definition as in formula (14). In this case, when a base is applied to the compound represented by formula (4) in step (c) of the present production method (2), the proton of the terminal alkyne is easily extracted by the base to generate a carbanion (so-called acetylide). Therefore, the carbon number can be easily increased by the nucleophilic substitution reaction of this carbanion with a haloalkane derivative represented by formula (5), and thereafter, an alkene derivative of the trans form (E form) represented by formula (2) can be easily obtained from the alkyne derivative represented by formula (1).

[0159] A more specific embodiment of the present production method (2) will be described below. The step (b) of the present production method (2) comprises reacting a compound represented by the following formula (13-2):

[0160] [ka]

[0161] As shown in the formula (4), 2-propyn-1-ol is reacted with 3,4-dihydro-2H-pyran (hereinafter sometimes referred to as "DHP") in the presence of an acid catalyst (here, p-toluenesulfonic acid (p-TsOH)) to protect the hydroxy group of 2-propyn-1-ol with a 2-tetrahydropyranyl group (tetrahydro-2H-pyran-2-yl group, hereinafter sometimes referred to as "THP") to obtain 2-(2-propynyloxy)tetrahydropyran (hereinafter sometimes referred to as "2-propyn-1-ol THP-protected compound") (the protecting group R in formula (4) is 2 Examples include THP.

[0162] Next, in step (c) of the present production method (2), after step (b), a compound represented by the following formula (14-2):

[0163] [ka]

[0164] As shown in the formula (5), the THP-protected 2-propyn-1-ol and the haloalkane derivative (wherein X in formula (5) is Br and R 1 Here, an example will be described in which is a substituent that does not react with solvated electrons. ) is coupled with to obtain 2-(2-alkynyloxy)tetrahydropyran (hereinafter, sometimes referred to as "carbon-enhanced 2-alkyn-1-ol THP protected product"). To explain this step (c) (coupling reaction) in detail, the proton of the terminal alkyne in the 2-propyn-1-ol THP protected product is abstracted with a base (here, n-butyl lithium (n-BuLi)) to generate a carbanion, which then nucleophilically attacks the haloalkane derivative to form S N The second reaction produces the carbon-multiplied 2-alkyn-1-ol THP-protected product.

[0165] Next, in step (a) of the present production method (2), after step (c), a compound represented by the following formula (10-2):

[0166] [ka]

[0167] As shown in the figure, an example is to react solvated electrons with the carbon-enhanced 2-alkyn-1-ol THP-protected compound to obtain a trans-form (E-form) alkene derivative. As mentioned above, in step (a), the carbon-carbon triple bond is reduced and -OTHP is eliminated to obtain a trans-form (E-form) alkene derivative.

[0168] The above is a specific embodiment of the present production method (2). When the carbon-enhanced 2-alkyn-1-ol THP-protected product is used as a starting material, the example of step (a) of the present production method (2) can also be regarded as an example of step (a) of the present production method (1).

[0169] In addition, in the step (b) of the present production method (2), the case where the hydroxy group of 2-propyn-1-ol is protected with a 2-tetrahydropyranyl group has been described as an example, but as described above, since it is sufficient that the elimination reaction in the step (a) proceeds, any protecting group can be used for protection, except for protecting groups that are deprotected by the action of solvated electrons. More preferred examples of protecting groups that can be used to protect the hydroxy group of 2-propyn-1-ol in the step (b) of the present production method (2) include 2-tetrahydropyranyl, methyl, methoxymethyl, tert-butyldimethylsilyl, ethoxyethyl, benzoyl, and acetyl groups, and more preferred are 2-tetrahydropyranyl, methyl, methoxymethyl, tert-butyldimethylsilyl, and ethoxyethyl groups, which are particularly suitable under conditions such as Birch reduction.

[0170] Here, a conventional example of a trans-form (E-form) alkene derivative obtained by the present production method (2) will be described below. Conventionally, propyne, not 2-propyn-1-ol, was used as a raw material, and the following formula (98):

[0171] [ka]

[0172] As an example, propyne and a haloalkane are coupled to obtain an alkyne derivative having a carbon atom.

[0173] Next, the following equation (99):

[0174] [ka]

[0175] An example is the production of a trans (E) alkene derivative from a carbon-added alkyne derivative by Birch reduction, as shown in the following formula:

[0176] Comparing the above conventional examples with the present production method (2), the present production method (2) has one more step for protecting the hydroxyl group, while the raw material of the present production method (2), 2-propyn-1-ol (propargyl alcohol) (about 10,000 yen per kg), is cheaper than the raw material of the conventional example, propyne (about 2 million yen per kg). Furthermore, according to the study by the present inventors, the yield of the alkene derivative obtained by the present production method (2) is about the same as that of the conventional example. Therefore, the present production method (2) can produce an alkene derivative more economically than the conventional method.

[0177] In addition, 2-propyn-1-ol THP-protected derivatives are also commercially available (approximately 100,000 yen per kg), and it is also possible to obtain a trans-form (E-form) alkene derivative starting from step (c) (the reaction represented by formula (14)) of the present production method (2) (i.e., to apply a production method in which steps (c) and (a) are carried out in that order). In this case, when comparing the present production method with the conventional example, the number of steps is the same and the raw materials are cheaper, so that the present production method can be produced more economically than the conventional method.

[0178] (Production method of (E)-6-octenal) As one of the more specific aspects of the present production method (2), a production method for (E)-6-octenal (hereinafter sometimes referred to as "the present octenal production method") will be described. The production method for the present octenal is the production method for the present production method (2) by removing the protecting group R 2 is THP, X in formula (5) is a bromine atom, and R 1 is replaced with a 4-(1,3-dioxolan-2-yl)butyl group (the substituent represented by the above formula (6) in which n is 4).

[0179] Each step included in the method for producing the present octenal will be specifically described below. The method for producing the present octenal includes a step of obtaining a THP-protected 2-propyn-1-ol from 2-propyn-1-ol (step (b) of the following formula (13-3):

[0180] [ka]

[0181] (c) a reaction represented by the following formula (14-3):

[0182] [ka]

[0183] and after this step, a step of subjecting 2-[7-(2-tetrahydropyranyloxy)-5-heptynyl]-1,3-dioxolane to a reduction reaction with solvated electrons to obtain 2-(5-heptenyl)-1,3-dioxolane (step (a); represented by the following formula (10-3):

[0184] [ka]

[0185] and after this step, a step of reacting 2-(5-heptenyl)-1,3-dioxolane with an acid to obtain (E)-6-octenal (step (d) represented by the following formula (11-3):

[0186] [ka]

[0187] According to the present method for producing octenal, (E)-6-octenal can be produced economically and in a high yield as compared to conventional methods.

[0188] (Method of producing (2E,6E)-2,6-octadienal) As one of the more specific aspects of the present production method (2), a production method for (2E,6E)-2,6-octadienal (hereinafter, sometimes referred to as "the present octadienal production method") will be described. The production method for the present octadienal is the production method for the present production method (2) by removing the protecting group R 2 is THP, X in formula (5) is a bromine atom, and R 1 is replaced with a 2-(1,3-dioxolan-2-yl)ethyl group (the substituent represented by the above formula (6) in which n is 2).

[0189] Each step included in the method for producing the present octadienal will be specifically described below. The method for producing the present octadienal includes a step of obtaining a THP-protected 2-propyn-1-ol from 2-propyn-1-ol (step (b) of the following formula (13-4):

[0190] [ka]

[0191] and after this step, a step of coupling the THP-protected 2-propyn-1-ol with 2-(2-bromoethyl)-1,3-dioxolane to obtain 2-[5-(2-tetrahydropyranyloxy)-3-pentynyl]-1,3-dioxolane (step (c); represented by the following formula (14-4):

[0192] [ka]

[0193] and after this step, a step of subjecting 2-[5-(2-tetrahydropyranyloxy)-3-pentynyl]-1,3-dioxolane to a reduction reaction with solvated electrons to obtain 2-(3-pentenyl)-1,3-dioxolane (step (a); represented by the following formula (10-4):

[0194] [ka]

[0195] (reaction represented by the following formula (11-4):) and, after this step, a step of reacting 2-(3-pentenyl)-1,3-dioxolane with an acid to obtain (E)-4-hexenal (step (d);

[0196] [ka]

[0197] (Reaction represented by the following formula (12-4):) and, after this step, a step of reacting (triphenylphosphoranylidene)acetaldehyde (Wittig reagent) with (E)-4-hexenal to obtain (2E,6E)-2,6-octadienal (step (e);

[0198] [ka]

[0199] According to the present method for producing octadienal, (2E,6E)-2,6-octadienal can be produced economically and in a high yield as compared to conventional methods. EXAMPLES

[0200] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0201] [Example 1] Production of (E)-2-octene by the present production method (1) Hereinafter, in the formula (1), -OR is attached to the carbon atom at the propargyl position. 2 (R 2 is "hydrogen atom" or "solvated electron" 2 Examples 1-1 to 1-7 show the results of the case where a -OR is bonded to the carbon atom at the propargyl position in the formula (1). 3 AND -OR 4 (R 3 and R 4 Both are due to the action of "hydrogen atoms" or "solvated electrons" 3 Between or 4 As an example of a case where a substituent that breaks the bond between the aryl group and the aryl group is bonded, the results are shown in Example 1-8.

[0202] <Example 1-1> In Example 1-1, the following formula (10-5):

[0203] [ka]

[0204] (In the above formula (1), R 2 is a 2-tetrahydropyranyl group).

[0205] A solution of 2-(2-octynyloxy)tetrahydropyran (hereinafter sometimes referred to as "2-octyn-1-ol THP protected product") (15.1 g, 72 mmol) prepared by a known method in tetrahydrofuran (THF, 20 mL) was placed in a 500 mL three-neck flask, and cooled to -60°C or lower using a dry ice-acetone bath and stirred. Ammonia was blown into the system from a cylinder to collect liquid ammonia (100 mL). Lithium (2.5 g, 360 mmol) was gradually added to the mixed solution at the same temperature, and the mixture was stirred at the same temperature for 0.5 hours after the addition, and the disappearance of the raw material was confirmed by gas-liquid chromatography. Unnecessary ammonia was removed by stirring overnight (8 to 12 hours, the same applies below) while gradually raising the temperature. A saturated aqueous solution of ammonium chloride (200 mL) was carefully dropped into the system while cooling it using an ice bath, and the aqueous layer was extracted with diethyl ether, and the obtained organic layer was washed with distilled water, then with saturated saline, and dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the filtrate was concentrated under normal pressure to obtain a crude product, which was then distilled under normal pressure to obtain (E)-2-octene (6.90 g, 85%). The (E)-2-octene obtained in Example 1-1 was purified to obtain Sample 1-1.

[0206] <<Physical properties of the obtained (E)-2-octene>> 1 H-NMR (CDCl3, 400MHz): 0.88 (3H), 1.04~1.49 (6H), 1.61 (3H), 1.94 (2H), 5.32~5.44 (2H) 13 C-NMR (CDCl3, 100MHz): 14.109, 17.911, 22.732, 29,514, 31.632, 32.784, 124.633, 131.814

[0207] <Example 1-2> In Example 1-2, the following formula (10-6):

[0208] [ka]

[0209] (In the above formula (1), R 2 is a methyl group).

[0210] In Example 1-2, (E)-2-octene was obtained in the same manner as in Example 1-1, except that the 2-octyn-1-ol THP protected product of Example 1-1 was replaced with 1-methoxy-2-octyne (hereinafter sometimes referred to as "2-octyn-1-ol Me protected product"). That is, 2-octyn-1-ol Me protected product (0.7 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.4 g, 72%). The (E)-2-octene obtained in Example 1-2 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0211] <Example 1-3> In Example 1-3, the following formula (10-7):

[0212] [ka]

[0213] (In the above formula (1), R 2 is a methoxymethyl group).

[0214] In Example 1-3, the 2-octyn-1-ol THP-protected product of Example 1-1 was replaced with 1-(methoxymethoxy)-2-octyne (hereinafter sometimes referred to as "2-octyn-1-ol MOM-protected product"), and the same method as in Example 1-1 was used to obtain (E)-2-octene. That is, the 2-octyn-1-ol MOM-protected product (0.85 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.49 g, 87%). The (E)-2-octene obtained in Example 1-3 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0215] <Example 1-4> In Example 1-4, the following formula (10-8):

[0216] [ka]

[0217] (In the above formula (1), R 2 The case where the tert-butyldimethylsilyl group is used will be explained below.

[0218] In Example 1-4, the THP-protected 2-octyn-1-ol of Example 1-1 was replaced with 1-(tert-butyldimethylsilyloxy-2-octyne (hereinafter sometimes referred to as "TBS-protected 2-octyn-1-ol"). In other words, a TBS-protected 2-octyn-1-ol (1.20 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.50 g, 89%). The (E)-2-octene obtained in Example 1-4 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0219] <Example 1-5> In Example 1-5, the following formula (10-9):

[0220] [ka]

[0221] (In the above formula (1), R 2 is an ethoxyethyl group) will be explained below.

[0222] In Example 1-5, the 2-octyn-1-ol THP protected product of Example 1-1 was replaced with 1-(ethoxyethoxy)-2-octyne (hereinafter sometimes referred to as "2-octyn-1-ol EE protected product"), but (E)-2-octene was obtained in the same manner as in Example 1-1. That is, 2-octyn-1-ol EE protected product (0.99 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.44 g, 80%). The (E)-2-octene obtained in Example 1-4 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0223] <Examples 1-6> In Examples 1-6, the following formula (10-10):

[0224] [ka]

[0225] (In the above formula (1), R 2 is a benzoyl group).

[0226] In Example 1-6, the THP-protected 2-octyn-1-ol of Example 1-1 was replaced with 1-(benzoyloxy)-2-octyne (hereinafter sometimes referred to as "Bz-protected 2-octyn-1-ol"). In other words, the Bz-protected 2-octyn-1-ol (1.13 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.05 g, 10%). The (E)-2-octene obtained in Example 1-4 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0227] <Example 1-7> In Examples 1-7, the following formula (10-11):

[0228] [ka]

[0229] (In the above formula (1), R 2 is an acetyl group) will be explained below.

[0230] In Example 1-7, the THP-protected 2-octyn-1-ol of Example 1-1 was used as 1-acetoxy-2-octyne (hereinafter, may be referred to as "Ac-protected 2-octyn-1-ol"). In other words, the Ac-protected 2-octyn-1-ol (0.85 g, 5.0 mmol) prepared by a known method was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (0.21 g, 37%). The (E)-2-octene obtained in Example 1-4 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0231] <Example 1-8> In Example 1-8, in the formula (1), R 3 and R 4 Here, the case where is a methyl group will be described. Here, the following formula (15):

[0232] [ka]

[0233] A process (first process) represented by the following formula (16):

[0234] [ka]

[0235] and a process (second process) represented by the following formula (10-12):

[0236] [ka]

[0237] (Step 3: step (a) of the present production method (1)).

[0238] <1st process> 2-Octyn-1-ol (0.15 g, 1.19 mmol) and dimethyl sulfoxide (DMSO, 2 mL) were placed in a 5 mL eggplant flask, and 2-iodoxybenzoic acid (IBX, 0.5 g, 1.79 mmol) was added. The mixture was heated and refluxed for 5.0 hours, and the disappearance of the raw material was confirmed by gas-liquid chromatography. After cooling, hexane (2 mL) was added to the system, followed by suction filtration. The filtrate was concentrated under reduced pressure to obtain a crude product of 2-octynal (0.15 g). This product was used in the next step 2 without further purification.

[0239] <Second process> The crude 2-octynal (0.15 g) and methanol (2 mL) were placed in a 10 mL eggplant flask, and p-toluenesulfonate pyridinium (PPTS, 36 mg, 0.14 mmol) was added and stirred for 24 hours at room temperature (20-25°C. The same applies below). After confirming the disappearance of the raw materials by gas-liquid chromatography, sodium hydrogen carbonate (20 mg) was added to the system and concentrated under reduced pressure. Distilled water was added to the residue, which was then extracted with diethyl ether, and the resulting organic layer was washed with saturated saline. After drying with anhydrous magnesium sulfate, the filtrate obtained by suction filtration was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography to obtain 1,1-dimethoxy-2-octyne (2-octynal dimethyl acetal, 0.18 g).

[0240] <3rd process> (E)-2-octene was obtained in the same manner as in Example 1-1, except that the THP-protected 2-octyne-1-ol of Example 1-1 was replaced with 1,1-dimethoxy-2-octyne in the third step of Example 1-8. That is, 1,1-dimethoxy-2-octyne (2.6 g, 15.27 mmol) prepared through the first and second steps was reacted in the same manner as in Example 1-1 to obtain (E)-2-octene (1.1 g, 64%). The (E)-2-octene obtained in Example 1-8 was, 1 H-NMR and 13 C-NMR confirmed that it was the same as standard 1-1.

[0241] [Comparative Example 1] Example (1) not applicable to formula (1) The following is -OR bonded to the propargyl carbon atom: 2 R 2 is "hydrogen atom" or "solvated electron" 2 As examples of the case where the substituent is "a substituent that cleaves the bond between the groups," the results are shown in Comparative Examples 1-1 to 1-3.

[0242] <Comparative Example 1-1> In Comparative Example 1-1, the compound represented by the following formula (90-1):

[0243] [ka]

[0244] (R 2 When is a hydrogen atom ) will be explained.

[0245] The reaction was carried out in the same manner as in Example 1-1, except that the THP-protected 2-octyn-1-ol of Example 1-1 was replaced with 2-octyn-1-ol in Comparative Example 1-1. However, 2-octyn-1-ol (1.0 g, 7.9 mmol) did not produce (E)-2-octene, but instead produced 2-octen-1-ol (0.82 g, 80%).

[0246] <Comparative Example 1-2> In Comparative Example 1-2, the compound represented by the following formula (90-2):

[0247] [ka]

[0248] (R 2 is a benzyl group) will be explained below.

[0249] In Comparative Example 1-2, the reaction was carried out in the same manner as in Example 1-1, except that the THP-protected 2-octyn-1-ol of Example 1-1 was replaced with 1-(benzyloxy)-2-octyne (hereinafter sometimes referred to as "Bn-protected 2-octyn-1-ol"). However, (E)-2-octene was not produced from the Bn-protected 2-octyn-1-ol (1.1 g, 5.0 mmol), and only 2-octen-1-ol (0.58 g, 90%) was produced.

[0250] <Comparative Example 1-3> In Comparative Example 1-3, the compound represented by the following formula (90-3):

[0251] [ka]

[0252] (R 2 The case where the alkyl group is a p-methoxybenzyl group will be explained below.

[0253] In Comparative Example 1-3, the reaction was carried out in the same manner as in Example 1-1, except that the THP-protected 2-octyn-1-ol of Example 1-1 was replaced with 1-(p-methoxybenzyloxy)-2-octyne (hereinafter sometimes referred to as "PMB-protected 2-octyn-1-ol"). However, (E)-2-octene was not produced from the PMB-protected 2-octyn-1-ol (1.2 g, 4.9 mmol), but 2-octen-1-ol (0.28 g, 45%) was produced.

[0254] [Comparative Example 2] Example (2) not corresponding to the above formula (1) In the following, -OR is attached to a carbon atom other than the propargyl carbon atom. 2 (R 2 is "hydrogen atom" or "solvated electron" 2 The results are shown in Comparative Example 2-1 as an example in which a substituent that does not break the bond between the aryl group and the alkyl group is bonded.

[0255] <Comparative Example 2-1> In Comparative Example 2-1, the compound represented by the following formula (90-4):

[0256] [ka]

[0257] The reaction represented by the following formula (96) (where m is 2) will be described.

[0258] The reaction was carried out in the same manner as in Example 1-1, except that the 2-octyn-1-ol THP protected product in Example 1-1 was replaced with the 3-nonyn-1-ol THP protected product in Comparative Example 1-3. However, (E)-2-octene was not produced from the 3-nonyn-1-ol THP protected product (1.0 g, 4.4 mmol), but the 3-nonyn-1-ol THP protected product (0.91 g, 91%) was produced. That is, if 2-(3-nonynyloxy)tetrahydropyran (3-nonyn-1-ol THP protected product) was used as a raw material and a reaction similar to that in Example 1 were assumed to occur, 3-nonene should have been produced, but the carbon-carbon triple bond was simply reduced, and 2-(3-nonenyloxy)tetrahydropyran (3-nonen-1-ol THP protected product) was produced.

[0259] [Example 2] Synthesis of (E)-6-octenal Hereinafter, the following formula (17):

[0260] [ka]

[0261] An example of the synthesis of (E)-6-octenal in the order shown below is shown.

[0262] <Example 2-1> Synthesis of THP-protected 2-propyn-1-ol (4d) 2-Propyn-1-ol (3d, 50 g, 892 mmol) and p-TsOH (0.5 g) were placed in a 300 mL 4-neck flask, and DHP (112.5 g, 1328 mmol) was added dropwise to the system while cooling to below 10 ° C using an ice bath and stirring. After 1.0 hour while warming to room temperature, the disappearance of the raw material was confirmed by gas-liquid chromatography, and a saturated aqueous solution of sodium bicarbonate was added to the system. After a separation operation, the aqueous layer was extracted with ethyl acetate, and the organic layer obtained was combined with the previous organic layer and washed with water and saturated saline. After drying with anhydrous magnesium sulfate, the filtrate obtained by suction filtration was concentrated under reduced pressure to obtain a crude product (132.3 g). Sodium carbonate (1.3 g) was added to this, and the product was purified by reduced pressure distillation to obtain a 2-propyn-1-ol THP protected product (4d, 112 g, yield 90%, boiling point 70-75 ° C / 1.3 kPa).

[0263] <Example 2-2> Synthesis of 2-[7-(2-tetrahydropyranyloxy)-5-heptyl]-1,3-dioxolane (1d) A 1L 4-neck flask was charged with a solution of 2-propyn-1-ol THP protected body (4d, 25.2g, 180mmol) in THF (150mL), and the mixture was cooled and stirred at -30°C under a nitrogen atmosphere. A n-butyllithium / hexane solution (1.57mol / L, 120mL, 190mmol) was added dropwise to the system over 40 minutes, the temperature in the system was raised to -10°C, and the mixture was stirred for another 1.0 hour. The temperature in the system was cooled again to -30°C, and a 1,3-dimethyl-2-imidazolidinone (40mL) solution of 2-(4-bromobutyl)-1,3-dioxolane (5d, 25g, 120mmol) was added dropwise. The mixture was stirred overnight while gradually increasing the temperature, and the disappearance of the raw material was confirmed by gas-liquid chromatography the next morning, and a saturated aqueous ammonium chloride solution was added and stirred for 30 minutes. After separation, the aqueous layer was extracted once with ethyl acetate, and the organic layer was washed with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the filtrate was concentrated under reduced pressure to obtain a crude product (47 g) of 2-[7-(2-tetrahydropyranyloxy)-5-heptyl]-1,3-dioxolane (1d). Sodium carbonate (0.47 g) was added to the crude product, and the residue obtained by cutting the front distillate under reduced pressure was used in the next step.

[0264] <Example 2-3> Synthesis of 2-(5-heptenyl)-1,3-dioxolane (2d) A solution of 2-[7-(2-tetrahydropyranyloxy)-5-heptynyl]-1,3-dioxolane (1d, 236 g, 720 mmol equivalent) obtained as the first distillation cut residue in tetrahydrofuran (220 mL) was placed in a 2 L 4-neck flask and cooled to -60 ° C or lower using a dry ice-acetone bath and stirred. Ammonia was blown into the system from a cylinder to collect liquid ammonia (1040 mL). Lithium (wire, 25 g, 3.6 mol) was added little by little to the mixed solution at the same temperature, and after the addition, the mixture was stirred at the same temperature for 0.5 hours, and the disappearance of the raw material was confirmed by gas-liquid chromatography. Unnecessary ammonia was removed by stirring overnight while gradually raising the temperature. A saturated aqueous solution of ammonium chloride (2000 mL) was carefully dropped into the system while cooling it using an ice bath, and the aqueous layer was extracted with diethyl ether, and the obtained organic layer was washed with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the filtrate was concentrated under reduced pressure (40°C / 400 Torr) and the residue, which contained about 20% diethyl ether, was transferred to a vacuum distillation apparatus. First, the degree of vacuum was carefully increased to remove the diethyl ether, and then the target compound was distilled out. In this way, 2-(5-heptenyl)-1,3-dioxolane (2d, 102.8 g, 2-step yield 85%, boiling point: 100-105°C / 2.0 kPa) was obtained.

[0265] <Example 2-4> Synthesis of (E)-6-octenal (7d) 2-(5-heptenyl)-1,3-dioxolane (2d, 102.5 g, 602 mmol), water (1450 mL), and acetic acid (600 mL) were placed in a 3 L, 4-necked eggplant flask and heated to 100°C with stirring. After reaching 100°C, the mixture was stirred for another 1.0 hour, at which point the reaction stopped at a conversion rate of about 95%, and the mixture was allowed to cool to room temperature while stirring was continued. Diethyl ether (500 mL) was added to the reaction solution, and the extraction procedure was repeated three times. The resulting organic layer was washed twice with water (1000 mL), twice with 10% aqueous sodium carbonate solution (1000 mL), and once with 10% saline (1000 mL), and then dried over anhydrous magnesium sulfate. The filtrate obtained after suction filtration was concentrated under normal pressure to remove as much diethyl ether as possible, and the residue was then distilled under reduced pressure to obtain (E)-6-octenal (7d, 42.1 g, 58%, boiling point 80-85°C / 5.3 kPa).

[0266] [Example 3] Synthesis example of (2E,6E)-2,6-octadienal Hereinafter, the following formula (18):

[0267] [ka]

[0268] This shows an example of synthesizing (2E,6E)-2,6-octadienal in the order shown in the figure. Note that the formula (18) also includes a step of synthesizing 2-propyn-1-ol THP protected body (4d) from 2-propyn-1-ol (3d), but this step is omitted because it is the same as in Example 2-1.

[0269] <Example 3-1> Synthesis of 2-[5-(2-tetrahydropyranyloxy)-3-pentynyl]-1,3-dioxolane (1e) A tetrahydrofuran (170 mL) solution of 2-propyn-1-ol THP protected body (4d, 29 g, 207 mmol) obtained in the same process as in Example 2-1 was placed in a 1L 4-neck flask, and cooled and stirred at -30 ° C under a nitrogen atmosphere. n-Butyl lithium / hexane (1.6 mol / L, 138 mL, 221 mmol) was added dropwise to the system over 40 minutes, the temperature in the system was raised to -10 ° C, and stirring was continued for another 1.0 hour. The temperature in the system was cooled again to -30 ° C, and a 1,3-dimethyl-2-imidazolidinone (46 mL) solution of 2-(2-bromoethyl)-1,3-dioxolane (5e, 25 g, 138 mmol) was added dropwise. The mixture was stirred overnight while gradually increasing the temperature, and the disappearance of the raw material was confirmed by gas-liquid chromatography the next morning, and a saturated aqueous ammonium chloride solution was added and stirred for 30 minutes. After the separation operation, the aqueous layer was extracted once with ethyl acetate, and the organic layer was washed with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the filtrate was concentrated under reduced pressure to obtain a crude product (45.5 g) of 2-[5-(2-tetrahydropyranyloxy)-3-pentynyl]-1,3-dioxolane (1e). Sodium carbonate (0.46 g) was added to the crude product, and the residue obtained by cutting the front distillate under reduced pressure was used in the next step.

[0270] <Example 3-2> Synthesis of 2-(3-pentenyl)-1,3-dioxolane (2e) A solution of 2-[5-(2-tetrahydropyranyloxy)-3-pentynyl]-1,3-dioxolane (equivalent to 1e, 138 mmol) obtained as the first distillation residue in tetrahydrofuran (42 mL) was placed in a 500 mL four-neck flask and cooled to -60 ° C or lower using a dry ice-acetone bath and stirred. Ammonia was blown into the system from a cylinder to collect liquid ammonia (200 mL). Lithium (wire, 5.76 g, 830 mmol) was added little by little to the mixed solution at the same temperature, and after the addition, the mixture was stirred at the same temperature for 0.5 hours, and the disappearance of the raw material was confirmed by gas-liquid chromatography. Unnecessary ammonia was removed by stirring overnight while gradually raising the temperature. A saturated aqueous solution of ammonium chloride (200 mL) was carefully dropped into the system while cooling it using an ice bath, and the organic layer obtained by extracting the aqueous layer with diethyl ether was washed with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the filtrate was concentrated under reduced pressure (40°C / 400 Torr) and the residue containing about 20% diethyl ether was transferred to a vacuum distillation apparatus. First, the degree of vacuum was carefully increased to remove the diethyl ether, and then the target compound was distilled out. In this way, 2-(3-pentenyl)-1,3-dioxolane (2e, 14 g, 2-step yield 71%, boiling point 75-80°C / 2.0 kPa) was obtained.

[0271] <Example 3-3> Synthesis of (E)-4-hexenal (7e) 2-(3-pentenyl)-1,3-dioxolane (2e, 5 g, 35.2 mmol), water (83 mL) and acetic acid (35 mL) were placed in a 3 L 4-necked eggplant flask and heated to 100°C with stirring. After reaching 100°C, the reaction was stirred for another 1.0 hour, at which point the reaction stopped at a conversion rate of about 95%, so stirring was continued while the mixture was allowed to cool to room temperature. Saturated saline (100 mL) was added to the reaction solution, and extraction with dichloromethane was repeated three times. The organic layer obtained was washed successively with water, 10% aqueous sodium carbonate solution and 10% saline, and then dried over anhydrous magnesium sulfate. The filtrate obtained after suction filtration was concentrated under normal pressure to obtain a crude product (8.8 g), which was used in the next step.

[0272] <Example 3-4> Synthesis of (2E,6E)-2,6-octadienal (8e) The crude product (8.8 g) of (E)-4-hexenal (7e) and acetonitrile (100 g) were placed in a 500 mL recovery flask and stirred. (Triphenylphosphoranylidene)acetaldehyde (16 g, 52.8 mmol) was added to the system and stirred at 70°C for 6.0 hours. After confirming the disappearance of the raw materials by gas-liquid chromatography, water (300 mL) was added to the system and extracted with pentane. The organic layer was concentrated under normal pressure, and the residue was purified by silica gel column chromatography to obtain (2E,6E)-2,6-octadienal (8e, 2.28 g, 52% yield for two steps).

Claims

1. (a) The following formula (1): 【Chemistry 1】 (In formula (1), the wavy line indicates the bonding position of the substituent, R 0 is any of the substituents shown in the parentheses in the formula, R 1 is an optional substituent, R 2 is a 2-tetrahydropyranyl group, a methyl group, a methoxymethyl group or an ethoxyethyl group, and R 3 and R 4 are methyl groups. A metal is dissolved in liquid ammonia, and the resulting electrons are solvated by ammonia to generate solvated electrons, which are then reacted with a compound represented by the following formula (2): 【Chemistry 2】 (In formula (2), R 1a is R in the formula (1) 1 If there is no part in it that reacts with the solvated electron, R 1 is the same substituent as R 1 If there is a moiety in the compound that reacts with the solvated electrons, the moiety is a substituent after the reaction; A method for producing an alkene derivative, comprising:

2. The method for producing an alkene derivative according to claim 1, Prior to the step (a), (b) The following formula (3): 【Chemistry 3】 The hydroxy group of the compound represented by the formula 2 (R 2 is R in the formula (1). 2 ) and is protected by the following formula (4): 【Chemistry 4】 (In formula (4), R 2 is R in the formula (1). 2 and obtaining a compound represented by the formula: After the step (b), (c) A compound represented by the formula (4) and a compound represented by the following formula (5): 【Chemistry 5】 (In formula (5), X is any halogen atom, and R 1 is R in the formula (1). 1 is the same substituent as that of the compound represented by formula (1), 【Chemistry 6】 (In formula (1a), R 1 and R 2 is R in the formula (1). 1 and R 2 and A method for producing an alkene derivative, comprising:

3. The method for producing an alkene derivative according to claim 1, R in the formula (1) 1 is expressed by the following formula (6): 【Chemistry 7】 (In formula (6), the wavy line indicates the bonding position of the substituent, and n is an integer of 1 or more.)

4. The method for producing an alkene derivative according to claim 3, The compound represented by formula (1) is represented by the following formula (1b): 【Chemistry 8】 (In formula (1b), R 2 is R in the formula (1). 2 and n is the same as in formula (6), In the step (a), a compound represented by the following formula (2b): 【Chemistry 9】 (wherein n is the same as in formula (1b)), After the step (a), (d) reacting an acid with the compound represented by formula (2b) to obtain a compound represented by the following formula (7): 【Chemistry 10】 (wherein n is the same as in formula (2b)), A method for producing an alkene derivative, comprising:

5. The method for producing an alkene derivative according to claim 4, In the formula (1b), n is 4, In the step (d), (E)-6-octenal is obtained as the compound represented by the formula (7).

6. The method for producing an alkene derivative according to claim 4, After the step (d), (e) reacting a Wittig reagent having an aldehyde group with the compound represented by formula (7) to obtain a compound represented by the following formula (8): 【Chemistry 11】 (wherein n is the same as in formula (7)), A method for producing an alkene derivative, comprising:

7. The method for producing an alkene derivative according to claim 6, In the formula (1b), n is 2; In the step (e), (2E,6E)-2,6-octadienal is obtained as the compound represented by formula (8), in accordance with the present invention.

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