Method for producing β-farnesenes and 2-(3-alkenyl)-1,3-butadiene compound having related structure, and synthetic intermediate compound thereof

Abstract

To provide an efficient method for producing β-farnesenes and their related derivatives, which can avoid problems of known synthesizing methods of β-farnesenes.SOLUTION: According to one aspect of the present invention, a method for producing a 2-(3-alkenyl)-1,3-butadiene compound (A) includes at least a step of obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by the following general formula (A) (where R1 and R2 are as defined above) by carrying out, in this order or in reverse order, a reductive removal reaction of an arene sulfonyl group W at an allyl position of a secondary allyl sulfone compound represented by the following general formula (G) (where R1 and R2 independently represent a hydrogen atom or a linear, branched, or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally having one or more unsaturated bonds, W represents an arene sulfonyl group, and Z represents a halogen atom) and an elimination reaction of hydrogen halide HZ.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing β-farnesenes, which are sesquiterpenes useful as fragrances or bioactive substances against insects and the like, and 2-(3-alkenyl)-1,3-butadiene compounds having related structures, and useful synthetic intermediate compounds.

Background Art

[0002] Among the long-known terpene compounds, farnesenes, there are α-type and β-type with different double bond positions. α-Farnesene has four geometric isomers of trisubstituted double bonds present at the 3rd and 6th positions, and β-farnesene has two geometric isomers of trisubstituted double bonds present at the 6th position.

[0003]

Chemical Formula

[0004] Among farnesenes, α-farnesene has been identified in many plants such as apples, pears, chrysanthemums ( Chrysanthemum ), perilla ( Perilla ), violas ( Yarrow ), etc. (3E,6E)-α-Farnesene is abundantly contained in the skin of apple fruits (serving as a natural source of this compound) and gives a green apple odor. (3Z,6E)-α-Farnesene is contained in the essential oils of plants such as perilla ( Perilla ) and gardenias ( Gardenia ). α-Farnesene is also contained in the extracts of many insects including multiple ants and cotton seed bugs ( Oxycarenus hyalinipennis ), etc., and various biological activities have been reported. For example, the red imported fire ant of the order Hymenoptera ( Solenopsis invictaIt includes trail pheromone of [[ID=]], alarm pheromone of the isopteran insect termite, aggregation pheromone of the dipteran insects Caribbean fruit fly and Mediterranean fruit fly (Ceratitis capitata Wiedemann), attractant of the lepidopteran insect codling moth, etc. In addition, β-farnesene is a component of essential oils of various plants and is known to have alarm pheromone activity against the hemipteran insect aphid. These natural and synthetic farnesenes are also used as fragrances (fragrance or flavor) for applications of biological activity to human olfaction.

[0005] β-Farnesenes are characterized by the 2-(3-alkenyl)-1,3-butadiene structure shown below.

[0006] [Chemical formula] (In the formula, R 1 , R 2 each independently represents a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds.)

[0007] β-Farnesenes correspond to the case where one of R 1 , R 2 is a methyl group and the other is a 4-methyl-3-pentenyl group. Other important related compounds having this characteristic structure are also known. As related compounds, for example, β-myrcene, which is the corresponding monoterpene, is known. Myrcenes (β-myrcene and its isomer α-myrcene shown below) are present in Laurel ), verbena ( Verbena ), caraway ( Dear) fennel (wild fennel; Fennel ) tarragon ( Artemisia ) inond ( Dill ) common thyme ( Angelica ) myrrh ( Myrcia ) pine ( Pine ) cardamom ( Ammonium ) peppermint ( Mint ) wormwood ( Sage ) galangal ( Hops ) hemp ( Cannabis ) etc. It is contained in plants. Also, myrcene is a pheromone of the beetle insect Anoplophora glabripennis( Beetles ) and acts as an attractant.

[0008]

Chemical formula

Prior art documents

Non-patent documents

[0009]

Non-patent document 1

Non-patent document 2

Non-patent document 3

Non-patent document 4

Non-patent document 5

Non-patent document 6

Non-patent document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

Problems to be Solved by the Invention

[0010] For basic research, applied research, and practical use of these farnesenes and their related derivatives, etc., it is necessary to synthesize and manufacture them economically. Although isomers that exist in large quantities in nature may be sold at low cost in some cases, non-natural isomers that do not exist in nature are supplied by synthesis. Also, it is possible to obtain various other isomers by isomerization of natural products, but they usually exist as complex isomer mixtures and involve great difficulties in isolating specific isomers and improving purity. For example, for basic research such as comparative studies of the activities of isomers and structure-activity relationship studies of derivatives with partially modified structures, etc., it is desired to selectively synthesize isomers such as the position of double bonds and geometric isomers, and the high degree of freedom applicable to the synthesis of derivatives with substituents replaced by others. For applications and practical use such as predicting the occurrence of organisms such as insects using pheromone activity and pest control, and applications to fragrances using fragrance activity for humans, etc., large-scale synthesis is required, and an efficient synthesis suitable for industrial scale-up is desired. In applications and practical use, it is not always necessary to use pure isomers, and in some cases, it may be more economically advantageous to use an isomer mixture with activity. For such purposes, an efficient manufacturing method for farnesenes and their related derivatives applicable to both basic and applied aspects has been strongly desired.

[0011] Various methods are known as synthetic methods for β-farnesenes. Many of the known methods give complex mixtures, and the isolation and purification of pure compounds from them involve great difficulties. For example, in Non-Patent Document 1, an α- and β-farnesene isomer mixture was obtained by the dehydration reaction of nerolidols, and the isomers were separated by florisil chromatography. Non-Patent Document 2 reported a synthesis in 8 steps from β-myrcene, Non-Patent Document 3 reported a synthesis in 12 steps starting from 2-(hydroxymethyl)-4-(phenylthio)-1-butene, and Non-Patent Document 4 reported a synthesis in 6 steps from linalool. Non-Patent Document 5 reported a 3-step synthesis from 3-methyl-3-butenol, Non-Patent Document 6 reported a 2-step synthesis from farnesol, Non-Patent Document 7 reported a 3-step synthesis starting from an unsaturated lactone, and Non-Patent Document 8 reported an efficient 3-step synthesis from β-myrcene. However, among these syntheses, the use of raw materials having a conjugated diene structure that is thermally and unstable in the presence of an acid, or syntheses that construct a conjugated diene structure at the intermediate stage in the early stage of synthesis (Non-Patent Documents 2, 7, 8, 9), the stability of the intermediate becomes a major problem in production on an industrial scale. In addition, syntheses using natural products as starting materials (Non-Patent Documents 2, 4, 6, 7, 8, 9) are limited to specific ones where the raw materials are available, and it is difficult to apply them to the synthesis of various derivatives with modified structures. Also, the use of highly toxic reagents such as selenium oxide in Non-Patent Document 2, mercury(II) acetate in Non-Patent Document 3, pyridinium chlorochromate (PCC) as a chromium oxidation reagent in Non-Patent Document 4, and hexamethylphosphoric triamide (HMPA) in Non-Patent Documents 3 and 5, and photoreactions (Non-Patent Document 9) that require special manufacturing equipment or reactions at low temperatures (Non-Patent Documents 2, 3, 5, 6, 9) are industrially difficult to carry out.

[0012] As described above, there are many problems with the known synthetic methods for β-farnesene, and there has been a strong demand for an efficient production method for β-farnesenes and their related derivatives that can avoid these problems.

Means for Solving the Problems

[0013] As a result of repeated consideration in view of the above circumstances, a secondary allyl sulfone compound described below was designed as a reasonable synthetic intermediate, and it was found that β-farnesene and related 2-(3-alkenyl)-1,3-butadiene compounds can be selectively and efficiently produced by a synthetic route applying this compound, thereby completing the present invention. Further, the production method according to the present invention can also be industrially advantageous.

[0014] According to one aspect of the present invention, the following general formula (G)

Chemical formula

Chemical formula

[0015] According to another aspect of the present invention, the following general formula (G)

Chemical formula

[0016] According to another aspect of the present invention, the following general formula (G) [Chemical formula] (In the formula, R 1 , R 2 Each independently represents a hydrogen atom, or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds. W represents an arenesulfonyl group, and Z represents a halogen atom.) By the elimination reaction of hydrogen halide HZ of the secondary allyl sulfone compound represented by the following general formula (E) [Chemical formula] (In the formula, R 1 , R 2 are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, and W represents an arenesulfonyl group.) A step of obtaining a secondary allyl sulfone compound represented by By the reductive elimination reaction of the arenesulfonyl group W at the allyl position of the obtained secondary allyl sulfone compound (E), the following general formula (A) [Chemical formula] (In the formula, R 1 , R 2 are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds.) A step of obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by A method for producing a 2-(3-alkenyl)-1,3-butadiene compound (A) is provided, which at least includes

[0017] According to another aspect of the present invention, the following general formula (G) [Chemical formula] (In the formula, R 1 , R 2 are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, W represents an arenesulfonyl group, and Z represents a halogen atom.) A secondary allyl sulfone compound represented by is provided

[0018] According to another aspect of the present invention, the following general formula (D’) [Chemical formula] (wherein one of R 1’ and R 2’ is a methyl group, the other is a 4-methyl-3-pentenyl group or a methyl group, and Z represents a halogen atom.) There is provided a halide compound represented by the formula: [Effect of the Invention]

[0019] According to the present invention, a 2-(3-alkenyl)-1,3-butadiene compound having a β-farnesene and related structure can be selectively and efficiently produced. [Modes for Carrying Out the Invention]

[0020] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited thereto.

[0021] In the chemical formulas of the intermediates, reagents and target compounds in this specification, when stereoisomers such as enantiomers (enantiomeric isomers) or diastereomers (diastereomeric isomers) may exist structurally, unless otherwise specified, each chemical formula represents all of these isomers in any case. Further, these isomers may be used alone or as a mixture in any ratio. In a mixture of enantiomers, a case where the enantiomers are present in a ratio of 50:50 is a racemic mixture, or a case where any one of the enantiomers is present in an excess ratio is a scalemic mixture, and either may be used.

[0022] The present inventors considered a synthetic plan as follows as a method for producing a 2-(3-alkenyl)-1,3-butadiene compound having a β-farnesene and related structure.

[0023] [Chemical Formula] [In the formula, the arrow pointing inwards represents a transform in retrosynthetic analysis, the pincer mark represents a bond to be disconnected in retrosynthetic analysis, and R 1 , R 2 are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, and X, Y, and Z each independently represent a halogen atom.]

[0024] In the above synthetic plan, when one of R 1 and R 2 is a methyl group and the other is a 4-methyl-3-pentenyl group, it corresponds to β-farnesene. More specifically, when R 1 is a methyl group and R 2 is a 4-methyl-3-pentenyl group, it is (E)-β-farnesene, and when R 1 is a 4-methyl-3-pentenyl group and R 2 is a methyl group, it corresponds to (Z)-β-farnesene.

[0025] First, in the synthesis of the target β-farnesene having a 2-substituted butadiene at the terminal and the 2-(3-alkenyl)-1,3-butadiene compound (A), the disconnection at the bond indicated by the above pincer is considered reasonable from the viewpoints of the availability of a C5 (carbon number 5) reagent based on the isoprene rule of terpenoids and the ease of derivative synthesis. For the carbon-carbon bond formation reaction between the intermediate building blocks (B) and (C), since the reaction points of bond formation are both at the allylic position and difficulties such as homocoupling on the nucleophile side and the electrophile side are expected in a normal Grignard coupling (carbon-carbon bond formation reaction between a Grignard reagent and a halide compound), the application of a method involving a carbon-carbon bond formation reaction by allylation of the anion at the α-position of the sulfone and a subsequent desulfonation reaction in a later step was considered as follows.

[0026] [Chemical formula] [In the formula, the hollow arrow represents a transform in retrosynthetic analysis, R 1 , R 2 are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, W is an arenesulfonyl group, and X, Y, and Z each independently represent a halogen atom.]

[0027] As important synthetic intermediates, secondary allyl sulfone compounds (G) and (H) were designed based on the difference in the position of the sulfone (arenesulfonyl group W). The secondary allyl sulfone compound (G) is obtained by the reaction of allylating the α-anion prepared from the primary allyl sulfone compound (I) with the dihalide compound (C), and the secondary allyl sulfone compound (H) is considered to be obtained by the reaction of allylating the α-anion prepared from the primary allyl sulfone compound (J) with the halide compound (B). The primary allyl sulfone compounds (I) and (J) can be synthesized from the halide compound (B) and the dihalide compound (C), respectively. That is, by converting either the compound (B) or the compound (C) into a sulfone compound and then allylating the prepared α-anion with the other, the secondary allyl sulfone compound (G) or (H) which is a key intermediate can be obtained.

[0028] By the reductive removal (desulfonation) of the arenesulfonyl group W at the allyl position of the secondary allyl sulfone compound (G) or (H), the halide compound (D) is obtained, and by the elimination of the hydrogen halide HZ of the halide compound (D), the 2-(3-alkenyl)-1,3-butadiene compound (A) is obtained. Or, by changing the order of functional group conversion, by the elimination of the hydrogen halide HZ from the secondary allyl sulfone compound (G) or (H), the secondary allyl sulfone compounds (E) or (F) are obtained respectively, and by the reductive removal (desulfonation) of the arenesulfonyl group W of the secondary allyl sulfone compound (E) or (F), the 2-(3-alkenyl)-1,3-butadiene compound (A) is obtained.

[0029] Many of the intermediates in the above synthetic plan (such as sulfone intermediates having exo-double bonds) are novel compounds and there are no reports on their synthesis examples and reaction examples. However, based on the above synthetic plan, intensive studies were carried out.

[0030] As a result of repeated studies based on the above considerations, the inventors of the present invention succeeded in realizing the target reaction and synthesizing β-farnesene with high efficiency and related 2-(3-alkenyl)-1,3-butadiene compounds. The embodiments of the present invention will be described in detail step by step below.

[0031] <The 2-(3-alkenyl)-1,3-butadiene compound which is the object of the present invention>

[0032] The β-farnesene which is the object of the present invention and the related 2-(3-alkenyl)-1,3-butadiene compound will be described. The 2-(3-alkenyl)-1,3-butadiene compound has the following general formula (A)

Chemical formula

[0033] The hydrocarbon groups R 1 and R 2is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 17 carbon atoms, more preferably 1 to 12 carbon atoms. Specifically, linear alkyl groups such as methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-icosyl group, etc., branched alkyl groups such as isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, and alkyl groups in which 1 to 6 hydrogen atoms of the above linear alkyl groups are substituted with methyl groups or ethyl groups, and cyclic alkyl groups containing a cyclic structure such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, etc. in the structure. Examples of the unsaturated bond contained in the hydrocarbon group R include a double bond and a triple bond, preferably a double bond. The preferred number of unsaturated bonds contained is 1 to 5. For example, R 1 、R 2 One of them is a methyl group, the other is a 4-methyl-3-pentenyl group or a methyl group, or R 1 、R 2 One of them is a phenyl group and the other is a hydrogen atom.

[0034] <Synthesis of starting material allyl sulfone compounds (I) and (J)>

[0035]

Chemical formula

[0036] The synthesis methods of the allyl sulfone compounds (I) and (J) which are the starting materials of the present invention are not particularly limited. For example, an arenesulfinate is mixed with an allyl halide compound (B) and a dihalide compound (C) having exo-methylene respectively, and heated in a solvent or the like to obtain by substituting the halogen atom X or Y at the allyl position with an arenesulfonyl group W. X of the allyl halide compound (B), Y and Z of the dihalide compound (C) are halogen atoms, preferably a chlorine atom, a bromine atom, or an iodine atom. More preferably, they are a chlorine atom or a bromine atom. As the allyl halide compound (B) and the dihalide compound (C), commercially available ones may be used, or those synthesized by known methods may be used. As the allyl halide compound (B), R 1 、R 2Each independently can be arbitrarily selected from a hydrogen atom corresponding to the target substance, or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms, which may contain one or more unsaturated bonds. It is preferable that X is a chlorine atom, a bromine atom or an iodine atom. Preferable specific examples of the dihalide compound (C) include 4-chloro-2-chloromethyl-1-butene, 2-bromomethyl-4-chloro-1-butene, 4-bromo-2-chloromethyl-1-butene, and 4-bromo-2-bromomethyl-1-butene. Instead of the halogen atoms X, Y, and Z, a phosphoryloxy group such as a dimethylphosphoryloxy group, a diethylphosphoryloxy group, or a diphenylphosphoryloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a nonafluorobutanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, etc., which are pseudo-halogen groups that function as leaving groups in the above substitution reaction, the alkylation of the α-anion (carbon-carbon bond formation reaction) described later, and the de-HZ reaction for olefin formation, can also be used, and are collectively referred to as halogen atoms in this specification (hereinafter the same). W in the allyl sulfone compounds (I) and (J) is an arenesulfonyl group. As the metal salts of the corresponding arenesulfinic acids used as reaction reagents, sodium benzenesulfinate and sodium p-toluenesulfinate are commercially available and industrially easy to obtain. Therefore, as the arenesulfonyl group W, a benzenesulfonyl group and a p-toluenesulfonyl group can be preferably exemplified. The regioselectivity of the conversion reaction from the dihalide compound (C) to the allyl sulfone compound (J) is high, and the halogen atom Y at the allyl position reacts preferentially compared to the halogen atom Z at the homoallyl position, and the allyl sulfone compound (J) can be obtained in good yield. Strictly speaking, WM 1 In, W is an arylsulfenyl group Ar―S(=O)-O- and the oxygen atom O is bonded to the metal atom M 1 And it is a compound in which S is bonded to a carbon atom C, and W in the sulfone compounds (I) and (J) is an arenesulfonyl group Ar―S(=O)2-.

[0037] <Allylation Step of Secondary Allyl Sulfone Compound (G) from Dihalide Compound (C) of Allyl Sulfone Compound (I)>

Chem.

Chem.

[0038] All of these allylation steps are allylation reactions at the α-position of the sulfone. The reaction is usually carried out in a solvent by generating the α-anion of the sulfone compound (I) with a base and then carrying out allylation with the dihalide compound (C) which is the allyl electrophile for the generated anion, or by generating the α-anion of the sulfone compound (J) and then carrying out allylation with the allyl halide compound (B) which is the allyl electrophile for the generated anion.

[0039]

Chem.

[0040] The base used for anion generation is not particularly limited as long as it can generate an anion at the α-position of the sulfone compound. Examples include inorganic bases such as sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium hydroxide, and potassium hydroxide; organic bases such as triethylamine, tributylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU); alkoxides such as sodium methoxide, sodium ethoxide, lithium tert-butoxide, and potassium tert-butoxide; alkyllithiums such as methyllithium, ethyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium; Grignard reagents such as methylmagnesium halide (including chloride, bromide, iodide, and the same hereinafter), ethylmagnesium halide, and phenylmagnesium halide; alkyl metal compounds such as dimethyldiethylzinc, diethyldiethylzinc, trimethylaluminum, triethylaluminum, and methylaluminum dichloride; and metal amides such as lithium diethylamide, lithium diisopropylamide, lithium isopropylcyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and halomagnesium hexamethyldisilazide. These can be used alone or in combination. Halide salts such as lithium chloride may be added. Particularly preferred bases are alkyllithiums, Grignard reagents, and metal amides.

[0041] As the electrophile used for allylation, X in the allyl halide compound (B) and Y and Z in the dihalide compound (C) are halogen atoms. Among the halogen atoms, chlorine atoms, bromine atoms, and iodine atoms are particularly desirable.

[0042] As the solvent, ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene, cumene, chlorine-based solvents such as methylene chloride, chloroform, trichloroethylene, nitriles such as acetonitrile, ketones such as acetone, 2-butanone, esters such as ethyl acetate, butyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc. may be mentioned, and a single solvent or a mixed solvent of two or more selected therefrom.

[0043] The reaction temperature can be appropriately selected according to the type of base used and the reaction conditions, but generally, -50°C to the boiling point temperature of the solvent is preferred, and -20°C to room temperature (5°C to 35°C, the same hereinafter) is more preferred.

[0044] The reaction time can be arbitrarily set, but the conversion rate and isomer ratio can be optimized by tracking with gas chromatography (GC) or thin layer chromatography (TLC). Usually, 5 minutes to 240 hours is preferred.

[0045] When the secondary allyl sulfone compounds (G) and (H) obtained in the above alkylation step or the halogen exchange step described later have sufficient purity and isomer ratio, they may be used in the next step as a crude product, but purification and separation of isomers can be appropriately selected from ordinary purification methods and isomer separation methods in organic synthesis such as distillation and various chromatographies.

[0046] Next, as a synthetic route from the obtained secondary allyl sulfone compound (G) or (H) to the 2-(3-alkenyl)-1,3-butadiene compound (A), the following two methods can be considered.

[0047] (I) A method via the halide compound (D), that is, (I)-(1) The allylic arenesulfonyl group W of the secondary allyl sulfone compound (G) or (H) is reductively cleaved (reductive cleavage or reductive removal) (desulfonation) to obtain the halide compound (D). (I)-(2) A method for obtaining the target 2-(3-alkenyl)-1,3-butadiene compound (A) by elimination of hydrogen halide HZ from the halide compound (D).

[0048]

Chemical formula

[0049] (II) A method via the secondary allyl sulfone diene compound (E) or (F), that is, (II)-(1) By elimination of hydrogen halide HZ from the secondary allyl sulfone compound (G) or (H) to obtain the secondary allyl sulfone diene compound (E) or (F). (II)-(2) A method for obtaining the target 2-(3-alkenyl)-1,3-butadiene compound (A) by reductive removal of the arenesulfonyl group W of the secondary allyl sulfone diene compound (E) or (F).

[0050]

Chemical formula

[0051] The synthetic routes (I) and (II) will be described in order, and their applications will be described later.

[0052] (I)-(1) <Reductive removal step of the allylic arenesulfonyl group W from the secondary allyl sulfone compound (G) or (H) to the halide compound (D)>

[0053] [Chemical formula] (In the formula, R 1 , R 2 , W, and Z are the same as above.)

[0054] This reductive removal step is a step of substituting the arenesulfonyl group W with a hydrogen atom H.

[0055] As the secondary allyl sulfone compound (G) or (H) which is the reaction substrate of the reductive removal step, a chloride compound (when Z = Cl), a bromide compound (when Z = Br), or an iodide compound (when Z = I) can be applied. They can be synthesized, for example, in the <halogen exchange step in the intermediate> described later. As the substrate of this reductive removal step, a chloride compound is preferable from the viewpoint of suppressing side reactions.

[0056] As the reductive removal reaction, a known method can be applied and is not particularly limited, but examples include a direct electron reduction reaction using a metal or metal salt, a nucleophilic substitution reduction reaction using a hydride (H - ) nucleophile, and a radical substitution reduction reaction using a hydrogen radical (H · ) reagent.

[0057] As reagents used in the direct electron reduction reaction by metals or metal salts, there are alkali metals such as sodium and lithium, other metals such as magnesium, zinc, and tin, and combinations of protic solvents such as lower amines like ammonia, methylamine, ethylamine, and propylamine, lower alcohols like methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, carboxylic acids like formic acid, acetic acid, and propionic acid, etc., as well as various metal amalgams and metal salts such as samarium diiodide. Preferred specific examples of metal-protic solvents include lithium-ammonia, sodium-ammonia, sodium-lower amine, lithium-lower amine, magnesium-methanol, and zinc-acetic acid. It is also preferable to use sodium naphthaleneide and Raney-Nickel (Raney-Ni) in a solvent. Examples of amalgams include sodium amalgam and aluminum amalgam. Among these, lithium-ammonia, sodium-ammonia, sodium-lower amine, lithium-lower amine, and magnesium-methanol are preferable in terms of ease of industrial implementation.

[0058] Hydride (H) used in the nucleophilic substitution reduction reaction -)Examples of nucleophilic reagents include borane compounds such as borane, alkylborane, dialkylborane, and bis(3-methyl-2-butyl)borane; silane compounds such as dialkylsilane and trialkylsilane; alane compounds such as alkylaluminum and dialkylaluminum (e.g., diisobutylaluminum hydride); metal hydrides such as sodium hydride, lithium hydride, potassium hydride, and calcium hydride; complex hydrides such as sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, sodium aluminum hydride, lithium aluminum hydride, sodium trimethoxyborohydride, lithium trimethoxyaluminum hydride, lithium diethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium triethylborohydride, and their alkoxy or alkyl derivatives. These complex hydrides can also be combined with formic acid to serve as a hydride source. For nucleophilic reduction reactions, transition metal catalysts may be used, examples of which include transition metal compounds such as nickel, rhodium, palladium, ruthenium, and iridium, with palladium compounds being particularly preferred. Preferred palladium compounds include zero-valent palladium compounds and divalent palladium compounds, and a phosphorus compound may also be used as a ligand together with these palladium compounds.Examples of phosphorus compounds used as ligands include phosphines such as trimethylphosphine, tri-tert-butylphosphine, trioctylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, dimethylphenylphosphine, tri(2-furyl)phosphine, diphenyl-2-pyridylphosphine, tris(hydroxymethyl)phosphine, 1,2-bis(dimethylphosphino)ethane, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,2-bis(dicyclohexylphosphino)ethane, 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, etc., and phosphites such as trimethyl phosphite, triethyl phosphite, triphenyl phosphite. Among these, the combination of complex hydride salts and palladium compounds is preferred. Furthermore, the combination of lithium triethylborohydride and a transition metal catalyst, and the combination of lithium borohydride, formic acid, and a transition metal catalyst are particularly preferred because high regioselectivity (in this case, S without allyl rearrangement. N 2 mechanism substitution reaction) can be achieved. The palladium compound used in this case is preferably a zero-valent one, but a divalent palladium compound is also preferred because a divalent metal compound is reduced to zero-valent in the reaction system under reducing conditions. As the hydrogen radical (H · ) reagent used in the radical substitution reduction reaction, tributyltin hydride (TBTH) etc. can be exemplified. For the radical reduction reaction, radical initiators such as azo compounds such as 2,2'-azobisisobutyronitrile, dimethyl-2,2'-azobis(isobutyrate), 1,1'-azobis(cyclohexanecarbonitrile), and organic peroxides such as di-tert-butyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide may be used in combination.

[0059] As solvents used in the reductive removal step, in addition to the above-mentioned protic solvents, for example, hydrocarbons such as water, hexane, heptane, benzene, toluene, xylene, cumene, etc., ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, 4-methyltetrahydropyran, etc., alcohols such as methanol, ethanol, 1-propanol, 2-propanol, t-butyl alcohol, benzyl alcohol, methoxyethanol, ethoxyethanol, etc., ketones such as acetone, 2-butanone, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as ethyl acetate, butyl acetate, etc., aprotic polar solvents such as N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), etc. can be mentioned. An appropriate one can be selected according to the type of reagent used and used alone or in combination. The reaction temperature in the reductive removal step varies depending on the reagent and solvent used, but is preferably from -78°C to 50°C, more preferably from -70°C to 20°C. The reaction time can be set arbitrarily, but it is desirable from the viewpoint of yield to complete the reaction by tracking the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC), and usually 5 minutes to 240 hours is preferred.

[0060] In the above reductive removal step, as a side reaction, not only the arenesulfonyl group W but also the halogen atom (halo group) Z may be reductively removed and substituted with a hydrogen atom. Therefore, excessive reagents and harsh reaction conditions should be avoided. By selecting an appropriate type of reagent and reaction conditions, the selectivity (reductively removing the arenesulfonyl group W while retaining the halo group Z) is good, and it has been found that the selectivity is particularly good when Z is a chlorine atom.

[0061] When the halide compound (D) obtained in the above reduction removal step or the halogen exchange step described below has sufficient purity and isomer ratio, it may be used in the next step as a crude product. However, purification and separation of isomers can be appropriately selected from ordinary purification methods and isomer separation methods in organic synthesis such as distillation and various chromatographies.

[0062] (I)-(2) <Desulfurization step of hydrogen halide HZ from the halide compound (D) to the 2-(3-alkenyl)-1,3-butadiene compound (A)>

[0063] [Chemical formula] (In the formula, R 1 , R 2 , Z are the same as above.)

[0064] This elimination step can usually be carried out by heating or cooling as necessary in a solvent or without a solvent to eliminate HZ.

[0065] As the halide compound (D) which is the reaction substrate of this elimination step, a chloride compound (when Z = Cl), a bromide compound (when Z = Br), and an iodide compound (when Z = I) can be applied. They can be synthesized, for example, in the <halogen exchange step in the intermediate> described below.

[0066] Examples of the base used in the detachment step include alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, sodium t-amyloxide, lithium methoxide, lithium ethoxide, lithium t-butoxide, lithium t-amyloxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, potassium t-amyloxide; hydrides such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; hydroxide salts such as sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide; carbonate salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; organometallic reagents such as methyllithium, ethyllithium, n-butyllithium, methylmagnesium chloride; metal amides such as lithium amide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium dicyclohexylamide; and organic bases such as triethylamine, diisopropylethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine, quinoline, pyrrolidine, piperidine, collidine, lutidine, morpholine, piperazine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). These bases can be used alone or in combination of multiple bases, and can be selected in consideration of the type, reactivity, and selectivity of the substrate. Among these bases, preferred examples include carbonate salts such as potassium carbonate; alkoxides such as potassium t-butoxide; and organic bases such as 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The amount of the base used is 0.01 to 100 moles, preferably 0.1 to 10 moles, per 1 mole of the halide compound (D) as the substrate.As solvents used in the elimination step, in addition to the above-mentioned protic solvents, for example, hydrocarbons such as water, hexane, heptane, benzene, toluene, xylene, cumene, etc., ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, 4-methyltetrahydropyran, etc., alcohols such as methanol, ethanol, 1-propanol, 2-propanol, t-butyl alcohol, benzyl alcohol, methoxyethanol, ethoxyethanol, etc., ketones such as acetone, 2-butanone, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as ethyl acetate, butyl acetate, etc., aprotic polar solvents such as N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), etc. can be mentioned. Appropriate ones can be selected according to the type of reagent used and can be used alone or in combination. The reaction temperature in the elimination step varies depending on the reagent and solvent used, but is preferably from -78°C to 200°C, more preferably from 0°C to 100°C. The reaction time can be arbitrarily set, but it is desirable in terms of yield to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) and complete the reaction. Usually, 5 minutes to 240 hours is preferable. Note that since the target 2-(3-alkenyl)-1,3-butadiene compound (A) contains a thermally unstable diene structure, high-temperature and long-time reactions should be avoided, and it is preferable to select mild conditions with low temperature and short time for the reaction to proceed.

[0067] Next, the synthetic route (II) will be described. The synthetic route (II) is (II)-(1) <Elimination step of hydrogen halide HZ from secondary allyl sulfone compound (G) or (H) to secondary allyl sulfone diene compound (E) or (F)>

[0068] [Chemical formula] (In the formula, R1 , R 2 , W, and Z are the same as above.)

[0069] (II)-(2) <Reductive removal step of the arenesulfonyl group W from the secondary allyl sulfone diene compound (E) or (F) to the 2-(3-alkenyl)-1,3-butadiene compound (A)>

[0070]

Chemical formula

[0071] Step (II)-(1) can be carried out by eliminating HZ in the same manner as in the above-mentioned (I)-(2) <Elimination step of hydrogen halide HZ from the halide compound (D) to the 2-(3-alkenyl)-1,3-butadiene compound (A)>. Step (II)-(2) can be carried out by reductively removing the arenesulfonyl group W at the allyl position in the same manner as in (I)-(1) <Reductive removal step of the arenesulfonyl group W at the allyl position from the secondary allyl sulfone compound (G) or (H) to the halide compound (D)>.

[0072] Among the synthetic routes described above, as a substrate for the reductive removal reaction (desulfonylation reaction) of the secondary arenesulfone present at the allyl position, the secondary allyl sulfone compound (G) in which the arenesulfone is located at the allyl position of the endo-olefin (trisubstituted double bond) is more suitable for the synthesis of β-farnesene and its related derivatives of the present invention from the viewpoints such as the regioselectivity of the reaction and the fact that it is a substrate without a thermally unstable conjugated diene structure compared to the secondary allyl sulfone compound (H) or (F) in which the arenesulfone is located at the allyl position of the exo-olefin (disubstituted double bond). This will be described in detail in the following examples.

[0073]

Chemical formula

[0074] <Halogen Exchange Step in Intermediate>

[0075] Among the secondary allyl sulfone compounds (G), secondary allyl sulfone compounds (H), and halide compounds (D) having a halogen atom (halo group) Z in the intermediate of this production method, three types of chloride compounds, bromide compounds, and iodide compounds can be considered depending on the type of the halogen atom Z. One of these halide compounds can be used as a raw material to synthesize another type of halide compound (halogen conversion reaction) and applied to the process. For the purpose of improving reactivity, conversion to a more reactive halide compound, for example, conversion from a chloride compound to a bromide compound, from a chloride compound to an iodide compound, or from a bromide compound to an iodide compound, is preferred. These can be selected in terms of yield, reactivity, stability of the intermediate, etc. The halogen exchange reaction involves reacting a starting halide compound (e.g., a chloride compound or a bromide compound) with a halide ion Z of a halogen present in a target compound having another halogen atom (e.g., a bromide compound or an iodide compound) - (e.g., Br - or I - ) and heating in a solvent with a halogen source such as a halide salt. Also, the halogen exchange reaction can be carried out within the system of the process ( in situation ). Note that the halogen exchange reaction can be carried out on any of the intermediates of the secondary allyl sulfone compound (G), secondary allyl sulfone compound (H), and halide compound (D), but in order to avoid unwanted side reactions (e.g., side reactions such as the halogen atom being reduced during the reductive removal step of the arenesulfonyl group W), it is preferably carried out on an appropriate intermediate. As an appropriate intermediate, the secondary allyl sulfone compound (G) or the halide compound (D) is preferred, and the halide compound (D) is particularly preferred.

[0076] Enumerating the advantages of the production method of the present invention described above, for example, (1) It has high process and storage stability during the synthesis of synthetic intermediates in order to construct an unstable conjugated diene structure at the final stage of synthesis or at a stage one step before that. (2) In the synthetic intermediate, when the substituents R 1 , R 2 or W are achiral, since there is no chiral carbon or only one chiral carbon (no multiple chiral carbon atoms) in the molecule, diastereomers derived from chiral carbon do not occur, and the purification and analysis of the intermediate are easier than the synthesis using a diastereomer mixture as the intermediate. (3) By selecting reagents and reaction conditions with good selectivity, the target product can be synthesized with high isomer purity. (4) It can be applied to the synthesis of various derivatives having the characteristic substituted butadiene structure of farnesenes. (5) For the purpose of utilizing biological activity, an isomer mixture can also be used as it is. In that case, an economical synthesis method may be advantageous even if the selectivity is low. (6) The obtained target product has high stability. It can be stored at room temperature. It can be purified by distillation or silica gel chromatography, which are common purification methods for organic compounds. etc. can be mentioned.

Example

[0077] Hereinafter, examples are shown to more specifically explain the present invention, but the present invention is not limited thereto.

[0078] Note that when using the value obtained by gas chromatography (GC) analysis as the purity of the raw material, product, and intermediate, it is denoted as %GC, and when using the value obtained by proton nuclear magnetic resonance ( 1 H-NMR) analysis, it is denoted as %NMR. The isomer ratio of the product and intermediate uses the ratio of GC analysis or 1 H-NMR analysis. GC conditions: GC: Shimadzu GC-14A, Column: 5% Ph-Me silicone 0.25mmφx25m, Carrier gas: He, Detector: FID.

[0079] The yield is the value of the converted yield based on %GC or %NMR. Since the raw materials used in the reaction and the products obtained in the reaction are not necessarily 100% pure, the converted yield (%) = {[(weight of the product obtained by the reaction × %GC) / molecular weight of the product] ÷ [(weight of the starting material in the reaction × %GC) / molecular weight of the starting material]} × 100. Note that since the detection sensitivity of gas chromatography varies depending on the compound, especially when the raw material or product is a crude product, the converted yield may exceed 100%.

[0080] Samples for spectral measurement of the compound were purified as necessary and used for measurement.

[0081] Synthesis Example <Synthesis of Primary Allyl Sulfone Compound Represented by the Following General Formula (I)>

[0082]

Chemical formula

[0083] Synthesis Example 1 Geranyl = p - Tolyl = Sulfone (geranyl p - tolyl sulfone) [when R 1 = CH3, R 2 = 4 - methyl - 3 - pentenyl group, and W = Ts = p - toluenesulfonyl group]

[0084]

Chemical formula

[0085] Under a nitrogen atmosphere, 80.0 g of sodium p-toluenesulfinate·tetrahydrate and 250 ml of dimethylformamide (DMF) were mixed. While cooling the mixture in an ice-water bath from time to time and stirring at 20 °C or lower, 55.0 g of geranyl bromide was added dropwise. After stirring at room temperature for 20 minutes, water was added to the mixture and it was extracted with n-hexane. After the usual post-treatment operations of washing, drying, and concentration from the n-hexane solution, 70.43 g of geranyl p-tolyl sulfone (93.8% GC, geometric isomer purity: E:Z = 94.9:5.1, yield 89%) was obtained.

[0086] Geranyl p-tolyl sulfone

Chemical formula

[0087] C 17 H 24 O2S Colorless oil. 1 1H-NMR (500 MHz, CDCl3): δ = 1.33 (3H, d, J = 1.3 Hz), 1.58 (3H, d, J = 0.8 Hz), 1.68 (3H, d, J = 1.0 Hz), 2.00 (4H, br.s), 2.43 (3H, s), 3.78 (2H, d, J = 7.8 Hz), 5.00 - 5.05 (1H, m), 5.17 (1H, dt-like, J = ~1.3, ~7.9 Hz), 7.31 (2H, d-like, J = ~8 Hz), 7.73 (2H, dt-like, J = ~2, ~8 Hz) ppm.

[0088] Synthesis Example 2 Neryl p-tolyl sulfone [When R in the general formula (I) 1 = 4-methyl-3-pentenyl group, R 2 = CH3, and W = Ts = p-toluenesulfonyl group]

[0089]

Chemical formula

[0090] Under a nitrogen atmosphere, 55.0 g of neryl bromide was added dropwise to a mixture of 95.0 g of sodium p-toluenesulfinate tetrahydrate and 250 ml of DMF, while cooling with an ice-water bath from time to time and stirring at 22 °C or lower. After stirring at room temperature for 29 hours, water was added to the mixture and extraction was carried out with n-hexane. After the usual post-treatment operations of washing, drying, and concentration from the n-hexane solution, 69.12 g of neryl p-tolyl sulfone (94.3% GC, geometric isomer purity: Z:E = 95.7:4.3, yield 84%) was obtained.

[0091] Neryl p-tolyl sulfone

Chemical formula

[0092] C 17 H 24 O2S Colorless oil. 1 1H-NMR (500 MHz, CDCl3): δ = 1.53 (3H, br.s), 1.64 (3H, d, J = 1.2 Hz), 1.72 (3H, d, J = 1.3 Hz), 1.74 - 1.79 (2H, m), 1.82 - 1.88 (2H, m), 2.43 (3H, s), 3.77 (2H, d-like, J = ~8 Hz), 4.91 - 4.97 (1H, m), 5.18 (1H, t-like, J = ~1.2, ~8 Hz), 7.31 (2H, d-like, J = ~8 Hz), 7.73 (2H, dt-like, J = ~2, ~8 Hz) ppm.

[0093] Synthesis Example 3 (E)-Cinnamyl phenyl sulfone [when R in the general formula (I) 1 = H, R 2 = Ph = phenyl group, and W = benzenesulfonyl group]

[0094] [Chemistry]

[0095] Under a nitrogen atmosphere, 25.0 g of cinnamyl bromide was added dropwise to a mixture of 95.0 g of sodium benzenesulphinate·dihydrate and 250 ml of dimethylformamide (DMF) while cooling in a water bath and stirring at 35 °C or lower. After stirring at room temperature for 48 hours, water was added to the mixture and it was extracted with diethyl ether. After the usual post-treatment operations of washing, drying, and concentration from the diethyl ether solution, 32.8 g of (E)-cinnamyl phenyl sulfone (99.3% NMR, containing 0.7% DMF), quantitative yield; was obtained.

[0096] (E)-cinnamyl phenyl sulfone [Chemistry]

[0097] C 15 H 14 O2S Yellow solid. IR (D-ATR): ν = 3083, 3057, 3028, 2976, 2906, 1672, 1586, 1498, 1478, 1446, 1403, 1319, 1293, 1238, 1159, 1136, 1085, 1055, 1026, 999, 982, 908, 813, 760, 739, 698, 690 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 3.95 (2H, dd, J = 7.6, 1.1 Hz), 6.11 (1H, dt, J = 15.9, 7.6 Hz), 6.37 (1H, d, J = 15.9 Hz), 7.25 - 7.33 (5H, m), 7.52 - 7.57 (2H, m), 7.62 - 7.67 (1H, m), 7.87 - 7.91 (2H, m) ppm. 1313C-NMR (125 MHz, CDCl3): δ = 60.46, 115.07, 126.58, 128.488, 128.497, 128.64, 129.07, 133.75, 135.70, 138.34, 139.19 ppm. GC-MS (EI, 70 eV): 51, 77, 91, 117 (base peak), 141, 164, 178, 193, 221, 258 (M + ).

[0098] Synthesis Example <Synthesis of Primary Allyl Sulfone Compound Represented by the Following General Formula (J)>

[0099]

Chemical Formula

[0100] Synthesis Example 4 Synthesis of 4-chloro-2-methylenebutyl p-tolyl sulfone (4-chloro-2-methylenebutyl p-tolyl sulfone) [When W = Ts = p-toluenesulfonyl group and Z = Cl in General Formula (J)]

[0101]

Chemical Formula

[0102] Under a nitrogen atmosphere, 12.51 g of 4-chloro-2-chloromethyl-1-butene was added dropwise to a mixture of 22.60 g of sodium p-toluenesulphinate·tetrahydrate and 120 ml of dimethylformamide (DMF) while cooling in an ice-water bath and stirring at 25°C or lower. After stirring at room temperature for 17 hours, 5.05 g of sodium p-toluenesulphinate·tetrahydrate was added and stirring was continued for another 3 days. Water was added to the mixture and extraction was carried out with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, 23.85 g of 4-chloro-2-methylenebutyl p-tolyl sulfone (96.7 - 89% NMR, containing 3.3 - 11% DMF, quantitative yield) was obtained. A part of this was subjected to spectrum measurement after removing DMF under vacuum.

[0103] 4-chloro-2-methylenebutyl p-tolyl sulfone

Chemical formula

[0104] C 12 H 15 ClO2S Colorless crystals Melting point [inflection point of the endothermic peak of DSC (differential scanning calorimeter), the same hereinafter]: 61.7°C IR (D-ATR): ν = 2985, 2946, 2929, 1647, 1598, 1494, 1448, 1418, 1405, 1381, 1315, 1308, 1298, 1274, 1237, 1206, 1170, 1147, 1121, 1086, 1034, 1020, 938, 920, 816, 804, 780, 709, 650, 637, 611, 516, 454 cm -1 . 11H-NMR (500 MHz, CDCl3): δ = 2.44 (3H, s), 2.68 (2H, t, J = 6.7 Hz), 3.64 (2H, t, J = 6.7 Hz), 3.78 (2H, s), 4.89 (1H, br.s), 5.15 (1H, br.s), 7.34 (2H, d-like, J = ~8 Hz), 7.74 (2H, d-like, J = ~8 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 21.61, 37.91, 42.07, 62.57, 122.44, 128.44, 129.67, 133.60, 135.12, 144.84 ppm. GC-MS (EI, 70 eV): 27, 41, 67 (base peak), 91, 105, 131, 155, 179, 194, 223, 241, 258 (M + ).

[0105] Synthesis Example 5 Synthesis of 4-chloro-2-methylenebutyl phenyl sulfone (when W = benzenesulfonyl group and Z = Cl in General Formula (J))

[0106] [Chemical Formula] (In the formula, Ph represents a phenyl group. The same applies hereinafter.)

[0107] In a nitrogen atmosphere, a mixture of 71.0 g of sodium benzenesulfinate dihydrate, 2.00 g of tetrabutylammonium chloride (TBAC), and 500 ml of acetonitrile was stirred at 50 °C, and 41.2 g of 4-chloro-2-chloromethyl-1-butene was added dropwise over 35 minutes. The mixture was heated to reflux at 80 - 95 °C for 6 hours and further stirred at room temperature for 2 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, a crude product was obtained. This crude product was recrystallized from ethyl acetate - n-hexane to obtain 63.54 g of 4-chloro-2-methylenebutyl phenyl sulfone (including 2.3% of TBAC by NMR, yield 89.4%). A part of this product was purified by silica gel column chromatography and used for spectral measurement.

[0108] 4-chloro-2-methylenebutyl phenyl sulfone

Chemical formula

[0109] C 11 H 13 ClO2S Colorless crystals Melting point: 45.1 °C IR (D-ATR): ν = 3086, 2970, 2927, 1649, 1585, 1479, 1447, 1409, 1317, 1294, 1273, 1237, 1203, 1168, 1145, 1118, 1084, 1029, 999, 939, 922, 888, 797, 784, 757, 712, 690, 651, 615, 531 cm -1 。 1 1H-NMR (500 MHz, CDCl3): δ = 2.70 (2H, t, J = 6.7 Hz), 3.65 (2H, t, J = 6.7 Hz), 3.81 (2H, s), 4.90 (1H, br.s), 5.16 (1H, br.s), 7.54 - 7.59 (2H, m), 7.64 - 7.68 (1H, m), 7.86 - 7.90 (2H, m) ppm. 1313C-NMR (125 MHz, CDCl3): δ = 37.92, 42.06, 62.55, 122.62, 128.48, 129.09, 133.49, 133.85, 138.07 ppm. GC-MS (EI, 70 eV): 51, 77, 91, 117 (base peak), 141, 164, 178, 193, 221, 258 (M + ).

[0110] Example <Synthesis of secondary allyl sulfone compound represented by the following general formula (G)>

[0111]

Chemical formula

[0112] Example 1 (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone [In the case of R 1 = CH3, R 2 = 4-methyl-3-pentenyl group, W = Ts = p-toluenesulfonyl group, Z = Cl] Synthesis

[0113]

Chemical formula

[0114] Under a nitrogen atmosphere, a mixture of 11.3 g (93.8% GC) of geranyl p-tolyl sulfone synthesized in Synthesis Example 1 above and 80 ml of tetrahydrofuran (THF) was cooled to -60 °C or lower and stirred while 13 ml of a 2.80 M solution of n-butyllithium in n-hexane was added dropwise. After stirring at this temperature for 30 minutes, a mixture of 7.0 g (95.0% NMR) of 2-bromomethyl-4-chloro-1-butene and 25 ml of THF was added dropwise over 20 minutes. The reaction temperature was gradually raised to room temperature and stirred for 15 hours. The reaction mixture was ice-cooled, diluted hydrochloric acid was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, 15.19 g (quantitative yield) of (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl p-tolyl sulfone was obtained.

[0115] (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl p-tolyl sulfone

Chemical Structure

[0116] C 22 H 31 ClO2S yellowish oil IR (D-ATR): ν = 2965, 2923, 1649, 1597, 1445, 1377, 1312, 1301, 1288, 1145, 1086, 898, 815, 739, 661, 584 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.18 (3H, d, J = 1.3 Hz), 1.58 (3H, s), 1.67 (3H, s), 1.92 - 1.98 (4H, m), 2.32 (1H, dd, J = 11.4, 14.3 Hz), 2.40 (2H, t, J = 7.2 Hz), 2.43 (3H, s), 2.93 (1H, br.d, J = ~13 Hz), 3.52 - 3.61 (2H, m), 3.84 - 3.91 [1H, m (ddd - like)], 4.84 (1H, s), 4.87 (1H, s), 4.87 - 4.92 (1H, br.d - like), 4.97 - 5.03 (1H, m), 7.30 (2H, d - like, J = ~8 Hz), 7.70 (2H, d - like, J = ~8 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 16.42, 17.63, 21.61, 25.64, 26.03, 33.87, 38.83, 39.60, 42.12, 63.34, 114.96, 117.11, 123.49, 129.27, 129.35, 131.91, 134.62, 140.74, 144.45, 145.59 ppm.

[0117] Example 2 Synthesis of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl p-tolyl sulfone [when in the general formula (G), R 1 = 4-methyl-3-pentenyl group, R 2 = CH3, W = Ts = p-toluenesulfonyl group, Z = Cl]

[0118]

Chemical formula

[0119] Under a nitrogen atmosphere, a mixture of 48.1 g (94.3% GC) of neryl = p - tolyl = sulfone synthesized in Synthesis Example 2 above and 250 ml of tetrahydrofuran (THF) was cooled to -60 °C or lower and stirred while 55.4 ml of a 2.80 M n - butyllithium - n - hexane solution was added dropwise. After stirring at this temperature for 45 minutes, 30.0 g (96.9% GC) of 2 - bromomethyl - 4 - chloro - 1 - butene was added dropwise over 40 minutes. The reaction mixture was stirred at this temperature for 2 hours. An aqueous ammonium chloride solution was added to the reaction mixture under ice - cooling to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post - treatment operations of washing, drying, and concentration from the ethyl acetate solution, a mixture of (Z)-1 - chloro - 7,11 - dimethyl - 3 - methylene - 6,10 - dodecadien - 5 - yl = p - tolyl = sulfone:(Z)-1-(2,6 - dimethyl - 1,5 - heptadienyl)-3 - methylene - cyclopentan - 1 - yl = p - tolyl = sulfone in a ratio of 85.8:14.1( 1 H - NMR) of 67.85 g (yield 86% in terms of the purity of the target product) was obtained.

[0120] The by - product (Z)-1-(2,6 - dimethyl - 1,5 - heptadienyl)-3 - methylene - cyclopentan - 1 - yl = p - tolyl = sulfone is formed by intramolecular alkylation and cyclization of the sulfone anion generated from the target product by an excess of base, suggesting that the use of an excess of base should be avoided.

[0121] A part of the mixture was purified by silica gel column chromatography and used for spectrum measurement.

[0122] (Z)-1 - chloro - 7,11 - dimethyl - 3 - methylene - 6,10 - dodecadien - 5 - yl = p - tolyl = sulfone

Chemical formula

[0123] C 22 H 31 ClO2S yellowish oil IR (D-ATR): ν = 2966, 2917, 2858, 1649, 1597, 1445, 1377, 1312, 1301, 1288, 1145, 1086, 901, 815, 738, 661, 580 cm -1 。 1 1H-NMR (500 MHz, CDCl3): δ = 1.46 - 1.52 (1H, m), 1.53 (3H, br.s), 1.64 (3H, d, J = ~1 Hz), 1.68 (3H, d, J = ~1 Hz), 1.68 - 1.83 (3H, m), 2.28 (1H, dd, J = 11.1, 14.1 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.43 (3H, s), 2.89 (1H, dd, J = 2.4, 14.1 Hz), 3.51 - 3.60 (2H, m), 3.88 (1H, dt, J = 3.1, 10.7 Hz), 4.87 - 4.94 (4H, m), 7.29 - 7.33 (2H, d-like, J = ~8 Hz), 7.68 - 7.72 (2H, d-like, J = ~8 Hz) ppm。 13 13C-NMR (125 MHz, CDCl3): δ = 17.63, 21.61, 23.21, 25.60, 25.83, 32.14, 34.14, 38.84, 42.14, 63.35, 115.39, 117.41, 123.46, 129.25, 129.38, 132.04, 134.67, 140.80, 144.48, 145.73 ppm。

[0124] Example 3 (E)-7-chloro-5-methylene-1-phenyl-1-hepten-3-yl phenyl sulfone [when R 1 = H, R 2 = Ph, W = benzenesulfonyl group, Z = Cl] synthesis

[0125]

Chemical Structure

[0126] Under a nitrogen atmosphere, a mixture of 17.4 g (99.3% GC) of (E)-cinnamyl=phenyl=sulfone synthesized in Synthesis Example 3 above and 150 ml of tetrahydrofuran (THF) was cooled to -60 °C or lower and stirred while 23.5 ml of a 2.80 M n-butyllithium-n-hexane solution was added dropwise. After stirring at this temperature for 1 hour, 13.53 g (91% GC) of 2-bromomethyl-4-chloro-1-butene was added dropwise over 40 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The reaction mixture was cooled with ice, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with diethyl ether. After the usual post-treatment operations of washing, drying, and concentration from the diethyl ether solution, followed by purification by silica gel column chromatography, 14.91 g (yield 64%) of (E)-7-chloro-5-methylene-1-phenyl-1-hepten-3-yl=phenyl=sulfone was obtained.

[0127] (E)-7-chloro-5-methylene-1-phenyl-1-hepten-3-yl=phenyl=sulfone

Chemical Structure

[0128] C 20 H 21 ClO2S Yellowish oil IR(D-ATR): ν = 3060, 3027, 2961, 1648, 1584, 1495, 1447, 1305, 1243, 1209, 1145, 1084, 968, 912, 755, 735, 690, 600 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 2.44 (2H, t, J = 7.1 Hz), 2.52 (1H, dd-like, J = 14.5, 11.5 Hz), 3.01 (1H, d-like, J = 14.5 Hz), 3.53 - 3.63 (2H, m), 3.78 - 3.84 (1H, m), 4.92 (1H, s), 4.94 (1H, s), 5.86 (1H, dd, J = 15.9, 9.4 Hz), 6.20 (1H, d, J = 15.9 Hz), 7.19 - 7.34 (5H, m), 7.48 - 7.54 (2H, m), 7.61 - 7.65 (1H, m), 7.82 - 7.87 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 33.58, 38.54, 42.10, 67.86, 115.80, 120.59, 126.55, 128.56, 128.62, 128.90, 129.26, 133.80, 135.64, 137.08, 138.45, 140.20 ppm.

[0129] Example <Synthesis of secondary allyl sulfone compounds represented by the following general formula (H)>

[0130]

Chemical formula

[0131] Example 4 (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = phenyl = sulfone [when R in the general formula (H) 1 = CH3, R 2 = 4-methyl-3-pentenyl group, W = benzenesulfonyl group, Z = Cl] synthesis

[0132]

Chemical formula

[0133] Under a nitrogen atmosphere, a mixture of 43.21 g (≥99% NMR) of 4-chloro-2-methylenebutyl=phenyl=sulfone synthesized in Synthesis Example 5 above and 500 ml of tetrahydrofuran (THF) was cooled to -65°C or lower and stirred while 70.0 ml of a 2.80 M n-butyllithium-n-hexane solution was added dropwise. After stirring at this temperature for 1 hour, 42.6 g of geranyl bromide was added dropwise over 30 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 30 hours. The reaction mixture was ice-cooled, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, and then purification by silica gel column chromatography, 36.4 g (yield 54%) of (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl=phenyl=sulfone was obtained.

[0134] (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl=phenyl=sulfone

Chemical Structure

[0135] C 21 H 29 ClO2S Yellowish oil IR (D-ATR): ν = 2965, 2918, 2856, 1644, 1585, 1447, 1377, 1305, 1205, 1146, 1084, 923, 823, 755, 721, 670, 615, 546 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.54 (3H, br.s), 1.56 (3H, br.s), 1.65 (3H, br.s), 1.89 - 2.03 (4H, m), 2.43 - 2.59 (3H, m), 2.75 - 2.81 (1H, m), 3.47 - 3.59 (3H, m), 4.90 - 4.95 (1H, m), 4.98 - 5.03 (1H, m), 5.10 (1H, s-like), 5.22 (1H, s-like), 7.52 - 7.57 (2H, m), 7.63 - 7.67 (1H, m), 7.84 - 7.88 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 16.20, 17.64, 25.65, 26.21, 26.38, 38.29, 39.52, 41.79, 70.56, 118.08, 120.42, 123.81, 128.87, 129.27, 131.63, 133.72, 137.08, 137.29, 139.06 ppm.

[0136] Example 5 (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone [in the general formula (H), R 1 = 4-methyl-3-pentenyl group, R 2 = CH3, W = p-toluenesulfonyl group, Z = Cl case] synthesis

[0137]

Chemical formula

[0138] Under a nitrogen atmosphere, a mixture of 17.1 g (96.0% NMR) of 4-chloro-2-methylenebutyl = p-tolyl = sulfone synthesized in Synthesis Example 4 above and 250 ml of tetrahydrofuran was cooled to -60 °C or lower and stirred while dropping 28.5 ml of a 2.80 M n-butyllithium-n-hexane solution. After stirring at this temperature for 30 minutes, 14.60 g (Z95.1% NMR) of neryl = bromide was dropped in over 10 minutes. The reaction mixture was gradually raised to room temperature and stirred for 15 hours. The reaction mixture was ice-cooled, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, and then purification by silica gel column chromatography, 19.1 g (yield 76%) of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone was obtained.

[0139] (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone

Chemical formula

[0140] C 22 H 31 ClO2S Colorless oil IR (D-ATR): ν = 2965, 2923, 2858, 1643, 1597, 1448, 1377, 1315, 1301, 1290, 1145, 1085, 922, 816, 735, 667, 593 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.59 (3H, br.s), 1.63 (3H, d, J = ~1.3 Hz), 1.67 (3H, br.s), 1.87 - 2.03 (4H, m), 2.41 - 2.58 (3H, m), 2.45 (3H, s), 2.74 - 2.81 (1H, m), 3.43 - 3.60 (3H, m), 4.93 (1H, t-like, J = ~8 Hz), 4.99 - 5.03 (1H, m), 5.11 (1H, s-like), 5.23 (1H, s-like), 7.33 (2H, dd-like, J = ~8.5, ~0.6 Hz), 7.72 (2H, dt-like, J = ~8.5, ~2 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.63, 21.63, 23.28, 25.73, 26.15, 26.25, 31.95, 38.56, 41.81, 70.72, 118.94, 120.28, 123.78, 129.28, 129.49, 131.94, 134.41, 137.12, 139.04, 144.69 ppm.

[0141] Example 6 Synthesis of 1-chloro-7-methyl-3-methylene-6-octen-4-yl p-tolyl sulfone [where R 1 = R 2 = CH3, W = p-toluenesulfonyl group, Z = Cl]

[0142]

Chemical formula

[0143] Under a nitrogen atmosphere, a mixture of 5.00 g (96.7% NMR) of 4-chloro-2-methylenebutyl p-tolyl sulfone synthesized in Synthesis Example 5 above and 80 ml of tetrahydrofuran was cooled to -60 °C or lower and stirred while dropping 7.35 ml of a 2.80 M n-butyllithium-n-hexane solution. After stirring at this temperature for 40 minutes, 3.35 g of prenyl bromide (1-bromo-3-methyl-2-butene) was dropped in over 5 minutes. The reaction mixture was gradually raised to room temperature and stirred for 16 hours. The reaction mixture was cooled with ice, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, followed by purification by silica gel column chromatography, 5.35 g of 1-chloro-7-methyl-3-methylene-6-octen-4-yl p-tolyl sulfone [97.4 - 98.7% GC (when the purity is described in a range, it indicates that the purity of the obtained multiple fractions was within that range. The same applies to the %GC and %NMR of the following purity descriptions.), containing 1.1 - 2.2% of the corresponding bromide, 1-bromo-7-methyl-3-methylene-6-octen-4-yl p-tolyl sulfone, yield 88%] was obtained.

[0144] 1-chloro-7-methyl-3-methylene-6-octen-4-yl p-tolyl sulfone

Chemical Structure

[0145] C 17 H 23 ClO2S yellowish oil IR (D-ATR): ν = 2967, 2917, 1643, 1597, 1450, 1378, 1315, 1301, 1289, 1144, 1086, 923, 816, 709, 667, 593 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.55 (3H, br.s), 1.63 (3H, d-like, J = ~1.2 Hz), 2.42 - 2.57 (3H, m), 2.44 (3H, s), 2.73 - 2.79 (1H, m), 3.47 - 3.52 (2H, m), 3.53 - 3.58 (1H, m), 4.88 - 4.93 (1H, m), 5.08 (1H, s-like), 5.21 (1H, s-like), 7.32 (2H, dd-like, J = ~8, ~1 Hz), 7.72 (2H, dt-like, J = ~8, ~2 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.85, 21.62, 25.63, 38.26, 38.38, 41.83, 70.49, 118.36, 120.25, 129.27, 129.48, 134.32, 135.32, 137.23, 144.69 ppm.

[0146] 1-Bromo-7-methyl-3-methylene-6-octen-4-yl = p-tolyl = sulfone

Chem.

[0147] C 17 H 23 BrO2S GC-MS (EI, 70 eV): 41, 79, 107 (base peak), 135, 170, 215, 217. GC-MS (CI, isobutane): 157, 215, 371, 373 (M + H + , base peak).

[0148] Example 7 Synthesis of 1-chloro-7-methyl-3-methylene-6-octen-4-yl = phenyl = sulfone [in the general formula (H), when R 1 = R 2 = CH3, W = benzenesulfonyl group, Z = Cl]

[0149]

Chem.

[0150] Under a nitrogen atmosphere, a mixture of 91.4 g (96% NMR) of 4-chloro-2-methylenebutyl phenyl sulfone synthesized in the same manner as in Synthesis Example 5 above and 800 ml of tetrahydrofuran was cooled to -60 °C or lower and stirred while dropping 150 ml of a 2.76 M n-butyllithium-n-hexane solution over 20 minutes. After stirring at this temperature for 35 minutes, 67.0 g of prenyl bromide (1-bromo-3-methyl-2-butene) was dropped over 20 minutes. The reaction mixture was gradually raised to room temperature and stirred for 16.5 hours. The reaction mixture was ice-cooled, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, 116.29 g (yield 99%) of 1-chloro-7-methyl-3-methylene-6-octen-4-yl phenyl sulfone was obtained.

[0151] 1-chloro-7-methyl-3-methylene-6-octen-4-yl phenyl sulfone

Chemical formula

[0152] C 16 H 21 ClO2S Yellowish oil IR (D-ATR): ν = 3064, 2965, 2916, 1673, 1643, 1585, 1447, 1377, 1304, 1244, 1146, 1085, 923, 755, 720, 690, 615 cm -1 。 1 1H-NMR (500 MHz, CDCl3): δ = 1.54 (3H, br.s), 1.63 (3H, d-like, J = ~1 Hz), 2.42 - 2.58 (3H, m), 2.73 - 2.82 (1H, m), 3.47 - 3.59 (3H, m), 4.88 - 4.93 (1H, m), 5.10 (1H, s-like), 5.22 (1H, s-like), 7.52 - 7.58 (2H, m), 7.62 - 7.67 (1H, m), 7.83 - 7.89 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.84, 25.64, 26.35, 38.33, 41.78, 70.49, 118.24, 120.41, 128.86, 129.25, 133.71, 135.47, 137.09, 137.32 ppm.

[0153]

Chem.

[0154] Example 8 (E)-7-chloro-5-methylene-1-phenyl-1-hepten-4-yl = p-tolyl = sulfone [when R 1 = H, R 2 = Ph = C6H5, W = p-toluenesulfonyl group, Z = Cl] synthesis

[0155]

Chem.

[0156] Under a nitrogen atmosphere, a mixture of 17.4 g (97% NMR) of 4-chloro-2-methylenebutyl = p-tolyl = sulfone synthesized in Synthesis Example 4 above and 150 ml of tetrahydrofuran was cooled to -60 °C or lower and stirred while adding dropwise 26.4 ml of a 2.80 M solution of n-butyllithium in n-hexane over 15 minutes. After stirring at this temperature for 1 hour, 14.6 g of cinnamyl bromide was added dropwise over 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled with ice, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, 26.03 g (quantitative yield) of crude (E)-7-chloro-5-methylene-1-phenyl-1-hepten-4-yl = p-tolyl = sulfone was obtained. This had sufficient purity and was used as a raw material for the next step as a crude product.

[0157] 7-chloro-5-methylene-1-phenyl-1-hepten-4-yl = p-tolyl = sulfone [Chemical]

[0158] C 21 H 23 ClO2S Colorless oil IR (D-ATR): ν = 3026, 2959, 2923, 2869, 1643, 1597, 1494, 1447, 1313, 1302, 1290, 1144, 1085, 967, 923, 816, 743, 708, 693, 669, 606, 588 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 2.45 (3H, s), 2.48 - 2.62 (2H, m), 2.68 - 2.76 (1H, m), 2.96 - 3.02 (1H, m), 3.51 - 3.61 (2H, m), 3.66 (1H, dd, J = 4.0, 11.4 Hz), 5.14 (1H, s), 5.27 (1H, s-like), 5.99 (1H, dt, J = 15.7, 7.2 Hz), 6.42 (1H, dt-like, J = 15.7, ~1.2 Hz), 7.18 - 7.22 (1H, m), 7.26 - 7.29 (4H, m), 7.34 (2H, d-like, J = ~8.5, ~0.6 Hz), 7.75 (2H, dt-like, J = ~8.5, ~1.9 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 21.65, 31.32, 38.32, 41.84, 70.37, 120.67, 124.06, 126.14, 127.54, 128.52, 129.37, 129.58, 133.53, 134.02, 136.69, 136.89, 144.93 ppm.

[0159] Synthesis Example 6 Synthesis of 1-chloro-3-methylenedodecan-4-yl = p-tolyl = sulfone

[0160] [Chemical]

[0161] Under a nitrogen atmosphere, a mixture of 41.58 g of 4-chloro-2-methylenebutyl = p-tolyl = sulfone (~97% NMR) synthesized in the same manner as in Synthesis Example 4 above and 500 ml of tetrahydrofuran was cooled to -60 °C or lower and stirred while dropping 65.5 ml of a 2.76 M n-butyllithium-n-hexane solution over 30 minutes. After stirring at this temperature for 40 minutes, 34.8 g of 1-bromooctane was dropped over 10 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was ice-cooled, an aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the usual post-treatment operations of washing, drying, and concentration from the ethyl acetate solution, and then purification by silica gel column chromatography, 51.1 g (yield 86%) of 1-chloro-3-methylenedodecan-4-yl = p-tolyl = sulfone was obtained.

[0162] 1-chloro-3-methylenedodecan-4-yl = p-tolyl = sulfone

Chemical formula

[0163] C 20 H 31 ClO2S Colorless solid Melting point: 52.5 °C IR (D-ATR): ν = 2954, 2925, 2855, 1642, 1597, 1494, 1456, 1379, 1313, 1302, 1289, 1145, 1086, 1019, 923, 815, 708, 667 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 0.86 (3H, t, J = 7.0 Hz), 1.13 - 1.37 (12H, m), 1.72 - 1.82 (1H, m), 1.98 - 2.08 (1H, m), 2.44 (3H, s), 2.45 - 2.53 (1H, m), 2.56 - 2.66 (1H, m), 3.50 (1H, dd, J = 11.7, 3.5 Hz), 3.56 (1H, dt-like, J = 11.7, 3.5 Hz), 3.61 (1H, ddd, J = 11.0, 7.5, 6.3 Hz), 5.01 (1H, s), 5.19 (1H, t-like, J = ~1.4 Hz), 7.32 (2H, dd-like, J = 0.6, 8.6), 7.70 (2H, dt-like, J = 8.2, ~2 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 14.07, 21.64, 22.59, 26.49, 27.12, 29.09, 29.15, 29.19, 31.74, 37.83, 41.90, 71.04, 119.92, 129.29, 129.46, 134.18, 137.33, 144.66 ppm.

[0164] Example <Synthesis of a Halide Compound Represented by the Following General Formula (D)>

[0165] [Chemical formula]

[0166] Example 9 Synthesis of (E)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene [when R 1 = CH3, R 2 = 4-methyl-3-pentenyl group, and Z = Cl in the general formula (D)]

[0167] [Chemical formula]

[0168] Under a nitrogen atmosphere, a mixture of 20.0 g of (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone (~100% NMR), which was synthesized in the same manner as in Example 1 above, 1.50 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride [(1,3-bis(diphenylphosphino)propane)palladium(II) chloride; PdCl2(dppp)2] and 200 ml of tetrahydrofuran was mixed while cooling with ice, and 61 ml of a 1.0 M solution of lithium triethylborohydride (Lithium triethylborohydride; Super-Hydride 登録商標 )-tetrahydrofuran solution was added dropwise over 35 minutes. After stirring at this temperature for 2 hours, 75 g of a 12.5% aqueous sodium hydroxide solution and then 11.3 g of 35% aqueous hydrogen peroxide were added dropwise. The reaction mixture was stirred for 20 minutes while cooling with ice. After filtering the reaction mixture through Celite 登録商標 ), the organic layer was separated. After the usual post-treatment operations of washing, drying, and concentration from the organic layer, and then purification by silica gel column chromatography, 9.22 g of (E)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene (80.4 - 97.6% GC, 97.2 - 99.1% E, yield 72%) was obtained.

[0169] (E)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene

Chemical formula

[0170] C 15 H 25 Cl Colorless oil. IR (D-ATR): ν = 2965, 2925, 2855, 1646, 1448, 1377, 1325, 1300, 1242, 1152, 1108, 984, 895, 834, 739, 661 cm -1 . 11H-NMR (500 MHz, CDCl3): δ = 1.61 (6H, br.s), 1.68 (3H, br.s.), 1.96 - 2.01 (2H, m), 2.03 - 2.11 (4H, m), 2.12 - 2.17 (2H, m), 2.50 (2H, t, J = 7.5 Hz), 3.61 (2H, t, J = 7.5 Hz), 4.82 (1H, br.s), 4.88 (1H, br.s), 5.07 - 5.15 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 16.02, 17.67, 25.67, 26.17, 26.65, 35.82, 39.16, 39.65, 42.80, 111.67, 123.54, 124.26, 131.32, 135.55, 145.55 ppm. GC-MS (EI, 70 eV): 27, 41, 55, 69 (base peak), 81, 93, 109, 121, 136, 169, 197, 240 (M + ).

[0171] Example 10 Synthesis of (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene [when R 1 = 4-methyl-3-pentenyl group, R 2 = CH3, Z = Cl] (1)

[0172]

Chemical formula

[0173] Under a nitrogen atmosphere, while mixing a mixture of 20.0 g (85.8% NMR) of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone synthesized in Example 2 above, 2.99 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride and 250 ml of tetrahydrofuran under ice cooling, 29.8 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 1 hour. The reaction temperature was gradually raised to room temperature and stirred for 14 hours. The reaction mixture was cooled with ice, and 70 g of a 12.5% aqueous sodium hydroxide solution and then 10 g of 35% hydrogen peroxide solution were added dropwise. The reaction mixture was extracted with diethyl ether. After the usual washing, drying, and concentration post-treatment operations from the diethyl ether solution, and then purification by silica gel column chromatography, 7.81 g (recovery rate 43.1%) of the raw material (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone and 3.05 g (99.3% GC, 91.5% Z, yield 29%; yield considering recovery 53%) of the target product (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene were obtained.

[0174] (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene

Chemical formula

[0175] C 15 H 25 Cl Colorless oil. IR(D-ATR): ν = 2964, 2927, 2856, 1646, 1449, 1376, 1325, 1242, 1152, 1109, 984, 895, 831, 738, 661 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.62 (3H, br.s), 1.69 (6H, s-like), 1.97 - 2.10 (6H, m), 2.10 - 2.17 (2H, m), 2.49 (2H, t, J = 7.5 Hz), 3.61 (2H, t, J = 7.5 Hz), 4.82 (1H, br.s), 4.87 (1H, br.s), 5.09 - 5.15 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.62, 23.34, 25.71, 26.08, 26.54, 31.98, 36.10, 39.19, 42.78, 111.63, 124.21, 124.33, 131.63, 135.74, 145.57 ppm. GC-MS (EI, 70 eV): 27, 41, 53, 69 (base peak), 81, 93, 109, 129, 156, 169, 197, 240 (M + ).

[0176] Example 11 Synthesis of (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene [when R 1 = 4-methyl-3-pentenyl group, R 2 = CH3, Z = Cl] (2)

[0177]

Chemical formula

[0178] Under a nitrogen atmosphere, while mixing a mixture of 1.95 g of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone (≥95% NMR) synthesized in Example 5 above, 0.145 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride and 40 ml of tetrahydrofuran under ice-cooling, 3.51 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 1 hour. After the reaction mixture was stirred under ice-cooling for 2.5 hours, 7.4 g of a 12.5% aqueous sodium hydroxide solution and then 1.2 g of 35% aqueous hydrogen peroxide were added dropwise. The reaction mixture was extracted with diethyl ether. After the usual post-treatment operations of washing, drying, and concentration from the diethyl ether solution, it was then purified by silica gel column chromatography. Target product (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene: Isomer of the target product (6Z,9E)-12-chloro-2,6,10-trimethyl-2,6,9-dodecatriene: Isomer of the target product (6Z,9Z)-12-chloro-2,6,10-trimethyl-2,6,9-dodecatriene = 8:38:54 mixture (total isomer yield 92%) was obtained.

[0179]

Chemical formula

[0180] As a reaction raw material for the target product (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene, as described above, a 5-position sulfone compound having a sulfone at the allylic position of a trisubstituted double bond, that is, (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone is excellent in stereospecificity and reaction selectivity. In contrast, for the 4-position sulfone compound having a sulfone at the allylic position of the exo-methylene group in this example, that is, (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone, it was suggested that a desulfonation reaction accompanied by allylic rearrangement (in this case, the movement of the double bond from the exo-position to the trisubstituted side) may occur concurrently, resulting in poor stereospecificity and reaction selectivity.

[0181] Synthesis Example 7 Synthesis of 2-(2-chloroethyl)-1-undecene

[0182]

Chemical formula

[0183] Under a nitrogen atmosphere, while mixing a mixture of 5.50 g of 1-chloro-3-methylenedodecan-4-yl = p-tolyl = sulfone synthesized in the above Synthesis Example 6, 0.440 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride and 150 ml of tetrahydrofuran under ice-cooling, 15.7 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 1 hour. The reaction mixture was stirred under ice-cooling for 100 minutes, and then 100 g of a 12.5% aqueous sodium hydroxide solution and then 11.5 g of 35% hydrogen peroxide solution were added dropwise. The separated organic layer was subjected to post-treatment operations of ordinary washing, drying and concentration, and then purified by silica gel column chromatography. Target product 2-(2-chloroethyl)-1-undecene: (E)-1-chloro-3-methyl-3-dodecene: isomer (Z)-1-chloro-3-methyl-3-dodecene of the target product = 4.7:46.5:48.8( 1 H-NMR) mixture (total yield of isomers 94%) was obtained.

[0184]

Chemical formula

[0185] In this synthesis example, similar to the above examples, the stereospecificity and reaction selectivity of the desulfonation reaction were low, and an isomer mixture with allyl rearrangement (the double bond moves from the exo-position to the trisubstituted side) was obtained.

[0186] The substrate of this reaction has the same substituents as the secondary sulfone compound of the general formula (H), that is, an exo-methylene group at the 3-position and an arylsulfonyl group at the 4-position. Therefore, in the synthesis of the halogen compound of the general formula (D), it was suggested that the synthesis by the desulfonation reaction of the secondary sulfone compound of the general formula (H) is not appropriate.

[0187] Example 12 Synthesis of (E)-7-chloro-5-methylene-1-phenyl-1-heptene [when R 1 =H, R 2 =Ph, Z = Cl in the general formula (D)]

[0188]

Chemical formula

[0189] Under a nitrogen atmosphere, while stirring a mixture of 5.00 g of 7-chloro-5-methylene-1-phenyl-1-hepten-3-yl=phenyl=sulfone synthesized in Example 3 above, 0.410 g of 1,3-bis(diphenylphosphino)propane palladium(II)=chloride and 100 ml of tetrahydrofuran, 18.0 ml of a 1.0 M lithium=triethylborohydride-tetrahydrofuran solution was added dropwise over 1 hour while cooling with ice. After stirring the reaction mixture for 1 hour under ice-cooling, 64 g of a 12.5% aqueous sodium hydroxide solution and then 7.0 g of 35% aqueous hydrogen peroxide solution were added dropwise. The separated organic layer was subjected to post-treatment operations such as ordinary washing, drying, and concentration, and then purified by silica gel column chromatography to obtain 2.02 g (97.0% GC, yield 66%) of the target product (E)-7-chloro-5-methylene-1-phenyl-1-heptene.

[0190] (E)-7-chloro-3-methylene-1-phenyl-1-heptene

Chemical formula

[0191] C 14 H 17 Cl Colorless oil. IR (D-ATR): ν = 3081, 3060, 3025, 2998, 2932, 2847, 1947, 1873, 1800, 1647, 1598, 1577, 1493, 1447, 1326, 1299, 1069, 1029, 964, 897, 743, 693, 658 cm -1 。 1 1H-NMR (500 MHz, CDCl3): δ = 2.22 (2H, t-like, J = ~8 Hz), 2.35 - 2.42 (2H, m), 2.54 (2H, dt, J = 0.6, 7.3 Hz), 3.64 (2H, t, J = 7.3 Hz), 4.88 (1H, s-like), 4.94 (1H, s-like), 6.22 (1H, dt, J = 15.9, 6.8 Hz), 6.42 (1H, d, J = ~16 Hz), 7.18 - 7.23 (1H, m), 7.28 - 7.38 (4H, m) ppm。 13 13C-NMR (125 MHz, CDCl3): δ = 31.10, 35.48, 39.10, 42.71, 112.10, 125.94, 126.94, 128.48, 129.77, 130.30, 137.60, 144.89 ppm。 GC-MS (EI, 70 eV): 39, 51, 65, 77, 91, 104, 117 (base peak), 129, 141, 157, 179, 191, 205, 220 (M + )。

[0192] Example <Synthesis of the secondary allyl sulfone compound represented by the following general formula (E)>

[0193]

Chemical formula

[0194] Example 13 (E)-7,11-Dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone [when R in the general formula (E) 1 = CH3, R 2 = 4-methyl-3-pentenyl group, W = p-toluenesulfonyl group] synthesis

[0195] [Chemical formula]

[0196] Under a nitrogen atmosphere, a mixture of 3.26 g of (E)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone (~100% NMR), 0.05 g of 2,6-di-t-butyl-p-cresol (BHT), and 6.30 g of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was stirred at 80 °C for 2 hours. After cooling the reaction mixture, it was extracted with ethyl acetate. The ethyl acetate solution was subjected to post-treatment operations such as normal washing, drying, and concentration to obtain 3.19 g of the target product (E)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone (quantitative yield).

[0197] (E)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone [Chemical formula]

[0198] C 22 H 30 O2S Yellowish oil IR (D-ATR): ν = 2967, 2924, 2856, 1596, 1446, 1382, 1313, 1301, 1288, 1144, 1086, 905, 815, 752, 670, 579 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.16 (3H, d, J = 1.3 Hz), 1.58 (3H, d, J = 0.6 Hz), 1.67 (3H, s), 1.89 - 1.99 (4H, m), 2.36 (1H, dd, J = 11.3, 13.8 Hz), 2.43 (3H, s), 3.23 (1H, d-like, J =~13 Hz), 3.96 (1H, dt-like, J =~2, 11 Hz), 4.89 - 4.92 (1H, m), 4.92 (1H, s), 4.97 - 5.03 (1H, m), 5.02 (1H, s), 5.08 (1H, d-like, J =~11 Hz), 5.26 (1H, d-like, J = 17 Hz), 6.29 (1H, dd, J = 11.0, 17.8 Hz), 7.30 (2H, d-like, J =~8 Hz), 7.73 (2H, d-like, J =~8 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 16.38, 17.63, 21.62, 25.64, 26.14, 30.38, 39.64, 63.25, 114.15, 117.20, 118.78, 123.62, 129.21, 129.35, 131.79, 134.98, 137.72, 141.25, 144.34, 145.55 ppm.

[0199] Example 14 (Z)-7,11-Dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone [where R in general formula (E) 1 = 4-methyl-3-pentenyl group, R 2 = CH3, W = p-toluenesulfonyl group] synthesis

[0200]

Chemical formula

[0201] Under a nitrogen atmosphere, while stirring a mixture of 20.0 g of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-5-yl = p-tolyl = sulfone synthesized in Example 2 above (85.8% NMR, containing 14.1% NMR of (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylene cyclopentane-1-yl = p-tolyl = sulfone as an impurity) and 50 ml of tetrahydrofuran, a mixture of 7.50 g of potassium tert-butoxide and 70 ml of tetrahydrofuran was added dropwise over 45 minutes while cooling with ice. After stirring the reaction mixture for 40 minutes under cooling, it was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate solution was subjected to post-treatment operations such as ordinary washing, drying, and concentration, and then purified by silica gel column chromatography to obtain the target product (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone and the isomer of the target product (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylene cyclopentane-1-yl = p-tolyl = sulfone present in the raw material in a ratio of 73:27( 1 H-NMR), and 15.48 g of a mixture (~73% NMR, yield 85% in terms of purity) was obtained.

[0202] A part of the mixture was purified by silica gel column chromatography and subjected to spectrum measurement.

[0203] (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone

Chemical formula

[0204] C 22 H 30 O2S Yellowish oil IR(D-ATR): ν = 2968, 2917, 2858, 1597, 1447, 1377, 1313, 1300, 1288, 1144, 1086, 906, 815, 752, 680, 578 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 1.40 - 1.75 (4H, m), 1.51 (3H, s), 1.63 (3H, br.s), 1.65 (3H, d-like, J = ~1 Hz), 2.33 (1H, dd, J = 11.1, 13.6 Hz), 2.43 (3H, s), 3.20 (1H, d-like m, J = ~13 Hz), 3.95 (1H, dt-like, J = ~2, 11 Hz), 4.85 - 4.95 (2H, m), 4.93 (1H, s), 5.03 (1H, s-like), 5.08 (1H, d-like, J = ~11 Hz), 5.23 (1H, d-like, J = 18 Hz), 6.27 (1H, dd, J = 10.9, 17.7 Hz), 7.29 - 7.33 (2H, m), 7.69 - 7.75 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.61, 21.61, 23.31, 25.57, 26.10, 30.67, 32.07, 63.05, 114.25, 117.40, 119.18, 123.63, 129.20, 129.36, 130.21, 131.78, 137.62, 141.12, 144.36, 145.80 ppm. GC-MS (EI, 70 eV, deformed peak): 41, 69 (base peak), 81, 91, 109, 113, 161, 187, 205.

[0205] Example <Synthesis of secondary allyl sulfone diene compound represented by the following general formula (F)>

[0206]

Chemical formula

[0207] Example 15 (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-4-yl = p-tolyl = sulfone [when R in general formula (F) 1 = 4-methyl-3-pentenyl group, R 2 = CH3, W = p-toluenesulfonyl group] synthesis

[0208] [Chemical]

[0209] Under a nitrogen atmosphere, a mixture of 5.00 g of (Z)-1-chloro-7,11-dimethyl-3-methylene-6,10-dodecadien-4-yl = p-tolyl = sulfone (~96% NMR), 0.03 g of 2,6-di-t-butyl-p-cresol (BHT), and 9.28 g of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) synthesized in the same manner as in Example 5 above was stirred at 40 - 60 °C for 3 hours. After cooling the reaction mixture, it was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was subjected to the usual post-treatment operations of washing, drying, and concentration, and then purified by silica gel column chromatography to obtain 3.09 g (yield 71%) of the target product (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-4-yl = p-tolyl = sulfone.

[0210] (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-4-yl = p-tolyl = sulfone [Chemical]

[0211] C 22 H 30 O2S Yellowish oil IR (D-ATR): ν = 3090, 2965, 2918, 2858, 1632, 1596, 1494, 1445, 1402, 1377, 1316, 1301, 1289, 1146, 1086, 1039, 1019, 986, 907, 815, 707, 670 cm -1 。 11H-NMR (500 MHz, CDCl3): δ = 1.60 (3H, d, J = 0.8 Hz), 1.62 (3H, d, J = 1.3 Hz), 1.69 (3H, br.s), 1.90 - 2.02 (4H, m), 2.42 (3H, s), 2.49 - 2.60 (1H, m), 2.88 - 2.98 (1H, m), 3.83 (1H, dd, J = 11.4, 3.7 Hz), 4.89 (1H, dt-like, J = 1.3, ~7 Hz), 4.96 (1H, d, J = 10.9 Hz), 5.01 - 5.08 (1H, m), 5.14 (1H, d, J = 17.5 Hz), 5.26 (1H, s), 5.41 (1H, d-like, J = 0.4 Hz), 6.28 (1H, ddd, J = 17.6, 10.9, 0.7 Hz), 7.23 - 7.32 (2H, m), 7.64 - 7.73 (2H, m) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 17.61, 21.58, 23.30, 25.71, 26.32, 26.62, 31.96, 65.87, 114.34, 119.02, 121.85, 123.85, 129.30, 129.32, 131.80, 134.85, 137.22, 138.57, 138.72, 144.38 ppm. GC-MS (EI, 70 eV, deformed peak): 41, 69 (base peak), 81, 91, 108, 133, 159, 183, 203, 358 (M + ).

[0212] Example 16 7-Methyl-3-methylene-1,6-octadien-4-yl = p-tolyl = sulfone [when R 1 = R 2 = CH3, W = p-toluenesulfonyl group] synthesis

[0213]

Chemical formula

[0214] Under a nitrogen atmosphere, a mixture of 1.00 g (97.4% GC) of 1-chloro-7-methyl-3-methylene-6-octen-4-yl = p-tolyl = sulfone synthesized in Example 6 above, 0.75 g of potassium tert-butoxide and 25 ml of tetrahydrofuran (THF) was stirred for 30 minutes under ice-cooling and then for 18 hours at room temperature. After cooling, the reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate solution was subjected to post-treatment operations such as ordinary washing, drying and concentration, and then purified by silica gel column chromatography to obtain 0.48 g (yield 55%) of the target product 7-methyl-3-methylene-1,6-octadien-4-yl = p-tolyl = sulfone.

[0215] 7-methyl-3-methylene-1,6-octadien-4-yl = p-tolyl = sulfone

Chemical formula

[0216] C 17 H 22 O2S 1 1H-NMR (500 MHz, CDCl3): δ = 1.57 (3H, s), 1.62 (3H, d-like, J = ~1.1 Hz), 2.42 (3H, s), 2.51 - 2.60 (1H, m), 2.88 - 2.95 (1H, m), 3.86 (1H, dd, J = 3.8, 11.3 Hz), 4.86 - 4.91 (1H, m), 4.95 (1H, d, J = 10.9 Hz), 5.12 (1H, d, J = 17.6 Hz), 5.26 (1H, s), 5.39 (1H, s), 6.24 (1H, ddd-like, J = 0.5, 10.9, 17.5 Hz), 7.25 - 7.32 (2H, m), 7.68 - 7.75 (2H, m) ppm. GC-MS (EI, 70 eV, deformed peak): 41, 55, 69, 77, 91 (base peak), 105, 119, 134, 157, 290 (M + )

[0217] Example <Synthesis of 2-(3-alkenyl)-1,3-butadiene compound represented by the following general formula (A)>

[0218]

Chem.

[0219] Example 17 Synthesis of (E)-β-farnesene [when R in general formula (A) 1 = CH3 and R 2 = 4-methyl-3-pentenyl group] (1)

[0220]

Chem.

[0221] Under a nitrogen atmosphere, a mixture of 9.31 g (98.9% GC) of (E)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene synthesized in the same manner as in Example 9 above, 0.03 g of 2,6-di-t-butyl-p-cresol (BHT), and 100 ml of tetrahydrofuran was stirred while being ice-cooled, and a mixture of 5.32 g of potassium tert-butoxide and 50 ml of tetrahydrofuran was added dropwise over 25 minutes. After the reaction mixture was stirred for 2.5 hours under ice-cooling, it was poured into an aqueous ammonium chloride solution and extracted with diethyl ether. The diethyl ether solution was subjected to the usual post-treatment operations of washing, drying, and concentration, and then distilled under reduced pressure to obtain 7.87 g (94.4 - 96.5% GC, quantitative yield) of the target product (E)-β-farnesene.

[0222] (E)-β-farnesene

Chem.

[0223] C 15 H 24 Colorless oil. Boiling point: 73 - 74 °C / 0.1 kPa IR (D-ATR): ν = 3089, 2967, 2926, 2856, 1595, 1442, 1377, 990, 893 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 1.61 (6H, br.s), 1.69 (3H, br.s.), 1.96 - 2.02 (2H, m), 2.04 - 2.11 (2H, m), 2.17 - 2.27 (4H, m), 5.00 (1H, br.s), 5.02 (1H, br.s), 5.06 (1H, d-like, J = ~11 Hz), 5.08 - 5.13 (1H, m), 5.15 - 5.19 (1H, m), 5.25 (1H, d-like, J = ~18 Hz), 6.38 (1H, dd, J = ~11, 18 Hz) ppm. 13 13C-NMR (125 MHz, CDCl3): δ = 16.01, 17.67, 25.68, 26.60, 26.70, 31.40, 39.69, 113.03, 115.70, 124.01, 124.35, 131.29, 135.37, 138.99, 146.12 ppm. GC-MS (EI, 70 eV): 27, 41, 55, 69 (base peak), 81, 93, 107, 120, 133, 148, 161, 175, 189, 204 (M + ).

[0224] Example 18 Synthesis of (E)-β-farnesene [when R 1 = CH3, R 2 = 4-methyl-3-pentenyl group] (2)

[0225]

Chemical formula

[0226] Under a nitrogen atmosphere, a mixture of 2.44 g of (E)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone (78.1% NMR, containing 21.9% NMR of (E)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentan-1-yl = p-tolyl = sulfone as an impurity), 0.80 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride and 25 ml of tetrahydrofuran was stirred while cooling with ice, and 12.0 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 1 hour. The reaction temperature was gradually raised to room temperature and stirred for 1 hour. The reaction mixture was cooled with ice, and 25 g of a 12.5% aqueous sodium hydroxide solution and then 3.75 g of 35% hydrogen peroxide solution were added dropwise. The reaction mixture was extracted with n-hexane. After the usual washing, drying, and concentration work-up operations from the n-hexane solution, and then purification by silica gel column chromatography, a 73:27 mixture of the target product (E)-β-farnesene and the cyclic isomer of the target product (E)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentane 1 H-NMR) of 1.04 g (57.5 - 67.2% GC, isomers total 83.4 - 92.5% GC, purity-converted yield 44%, purity-converted isomers total yield 63%) was obtained.

[0227] (E)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentane [Chemical formula]

[0228] C 15 H 24 Colorless oil. 13 C-NMR(150MHz,CDCl3):δ=16.47,17.83,25.84,26.84,32.52,33.88,39.20,39.78,40.78,104.96,124.46,129.07,131.48,134.74,153.01ppm. GC-MS (EI, 70 eV): 27, 41, 55, 69 (base peak), 81, 93, 107, 123, 135, 148, 161, 176, 189, 204 (M + )。

[0229] Example 19 Synthesis of (E)-β-farnesene [when R 1 = CH3 and R 2 = 4-methyl-3-pentenyl group] (3)

[0230]

Chemical formula

[0231] Under a nitrogen atmosphere, while stirring a mixture of 2.50 g of (E)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone (~100% NMR), 0.05 g of 2,6-di-t-butyl-p-cresol (BHT), and 40 ml of methanol at room temperature, 1.70 g of metallic magnesium was added all at once. Hydrogen generation was observed at the start of the reaction, and the reaction mixture exothermed up to 37 °C. The exotherm due to this initial reaction heat was suppressed to 30 - 37 °C with an ice bath, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, 10% hydrochloric acid was added, and the mixture was extracted with diethyl ether. After the usual post-treatment operations of washing, drying, and concentration from the diethyl ether solution, the target product (E)-β-farnesene: a 66.5:33.5 (GC) mixture of an isomer (E)-7,11-dimethyl-3-methylene-1,5,9-dodecatriene in which the trisubstituted double bond at the 6-position of the target product has migrated to the (E)-disubstituted double bond at the 5-position, 1.34 g (quantitative yield in total of isomers) was obtained.

[0232] (E)-7,11-dimethyl-3-methylene-1,5,9-dodecatriene

Chemical formula

[0233] C 15 H 24 Colorless oil. 13 C-NMR (150 MHz, CDCl3): δ = 17.82, 20.93, 25.87, 26.04, 34.79, 36.55, 37.35, 113.70, 116.42, 124.92, 125.73, 131.32, 138.48, 138.91, 145.65 ppm. GC-MS (EI, 70 eV): 27, 41, 55, 67, 69, 79 (base peak), 81, 93, 105, 119, 133, 147, 161, 175, 189, 204 (M + ).

[0234] Example 20 Synthesis of (Z)-β-farnesene [in the general formula (A), when R 1 = 4-methyl-3-pentenyl group, R 2 = CH3] (1)

[0235]

Chemical formula

[0236] Under a nitrogen atmosphere, a mixture of 1.81 g (97% GC) of (Z)-12-chloro-2,6-dimethyl-10-methylene-2,6-dodecadiene synthesized in Example 10 above, 0.03 g of 2,6-di-t-butyl-p-cresol (BHT), and 4.60 g of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was stirred at 80 °C for 4.5 hours. After cooling the reaction mixture, it was poured into dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether solution was subjected to the usual post-treatment operations of washing, drying, and concentration, and then distilled under reduced pressure to obtain 1.37 g of the target product (Z)-β-farnesene (97.9 - 98.1% GC, 94.3 - 95.8% Z, yield 92%).

[0237] (Z)-β-farnesene

Chemical formula

[0238] C 15 H 24 Colorless oil IR (D-ATR): ν = 3089, 2966, 2928, 2857, 1595, 1448, 1376, 990, 893 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 1.61 (3H, br.s), 1.69 (3H, br.s.), 1.70 (3H, t, J = ~1 Hz), 1.99 - 2.10 (4H, m), 2.15 - 2.25 (4H, m), 5.00 (1H, s-like), 5.01 (1H, s-like), 5.06 (1H, dq-like, J = ~11, ~1 Hz), 5.09 - 5.14 (1H, m), 5.15 - 5.19 (1H, m), 5.25 (1H, dt-like, J = ~18, ~0.6 Hz), 6.38 (1H, dd, J = ~11, 18 Hz) ppm 13 13C-NMR (125 MHz, CDCl3): δ = 17.62, 23.36, 25.70, 26.51, 26.60, 31.66, 31.97, 113.08, 115.66, 124.29, 124.82, 131.57, 135.53, 138.95, 146.15 ppm GC-MS (EI, 70 eV): 27, 41, 55, 69 (base peak), 81, 93, 107, 120, 133, 148, 161, 175, 189, 204 (M + ).

[0239] Example 21 Synthesis of (Z)-β-farnesene [when R in general formula (A) 1 = 4-methyl-3-pentenyl group, R 2 = CH3]

[0240]

Chemical formula

[0241] Under a nitrogen atmosphere, while stirring a mixture of 4.88 g of (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-4-yl = p-tolyl = sulfone (≥95% NMR) synthesized in Example 15 above, 0.03 g of 2,6-di-t-butyl-p-cresol (BHT), 0.29 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride, and 80 ml of tetrahydrofuran, 3.5 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was injected over 5 minutes while stirring under ice cooling. After stirring the reaction mixture under ice cooling for 45 minutes, 7.5 g of a 12.5% aqueous sodium hydroxide solution and then 1.20 g of 35% hydrogen peroxide solution were added dropwise. 20 ml of water was added to the reaction mixture, and the organic layer was separated. After the usual post-treatment operations of washing, drying, and concentration from the organic layer, in addition to the target (Z)-β-farnesene, a complex isomer mixture containing the isomer of the target, (E)-β-farnesene, (Z,Z)-3,7,11-trimethyl-1,3,6,10-dodecatetraene, (Z)-α-farnesene, and other isomers, etc., 1.36 g of a crude product was obtained.

[0242] Example 22 Synthesis of (Z)-β-farnesene [when R in the general formula (A) 1 = 4-methyl-3-pentenyl group, R 2 = CH3] (3)

[0243]

Chemical formula

[0244] Under a nitrogen atmosphere, a mixture of 5.89 g of (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone synthesized in Example 14 above (approx. 59% GC [approximate value because decomposition occurs in GC], containing ≧~40% GC [approximate value because decomposition occurs in GC] of (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentan-1-yl = p-tolyl = sulfone as an impurity), 2.00 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride, and 60 ml of tetrahydrofuran was stirred while being ice-cooled, and 19.3 ml of a 1.7 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 30 minutes. The reaction temperature was gradually raised to room temperature and stirred for 16 hours. The reaction mixture was ice-cooled, and 40.2 g of a 12.5% aqueous sodium hydroxide solution and then 6.05 g of 35% hydrogen peroxide solution were added dropwise. Water was added to the reaction mixture, and it was extracted with diethyl ether. After the usual post-treatment operations of washing, drying, and concentration from the diethyl ether solution, 3.92 g of a crude product was obtained as a mixture of the target product (Z)-β-farnesene and the cyclic isomer of the target product (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentane in a ratio of 59:42 (GC), along with a mixture of isomers containing multiple minor isomers.

[0245] (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentane

Chemical formula

[0246] Example 23 Synthesis of (Z)-β-farnesene [when R 1 = 4-methyl-3-pentenyl group, R 2 = CH3]

[0247]

Chemical formula

[0248] Under a nitrogen atmosphere, a mixture of 9.00 g of (Z)-7,11-dimethyl-3-methylene-1,6,10-dodecatrien-5-yl = p-tolyl = sulfone synthesized in Example 14 above (approx. 51% GC [approximate value because decomposition occurs in GC], containing (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentan-1-yl = p-tolyl = sulfone as an impurity), 1.48 g of 1,3-bis(diphenylphosphino)propane palladium(II) chloride, and 80 ml of tetrahydrofuran was stirred while being ice-cooled, and 55.2 ml of a 1.0 M lithium triethylborohydride-tetrahydrofuran solution was added dropwise over 30 minutes. The reaction temperature was gradually raised to room temperature and stirred for 17 hours. The reaction mixture was ice-cooled, and 68.5 g of a 12.5% aqueous sodium hydroxide solution and then 10.3 g of 35% hydrogen peroxide solution were added dropwise. Water was added to the reaction mixture, and it was extracted with diethyl ether. After the usual washing, drying, and concentration post-treatment operations from the diethyl ether solution, 5.10 g of a crude product was obtained as a complex isomer mixture containing the target product (Z)-β-farnesene, the cyclic isomer (Z)-1-(2,6-dimethyl-1,5-heptadienyl)-3-methylenecyclopentane of the target product in a ratio of 59:42, and a plurality of minor isomers.

[0249] Example 24 (E)-3-Methylene-7-phenyl-1,6-heptadiene [When R in the general formula (A) 1 = H, R 2 = Ph = phenyl group] Synthesis

[0250]

Chemical formula

[0251] Under a nitrogen atmosphere, 610 μl of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to a mixture of 500 mg (97% GC) of (E)-7-chloro-5-methylene-1-phenyl-1-heptene synthesized in Example 12 above, 50 mg of sodium bromide, and 8 ml of N-methyl-2-pyrrolidone. The reaction mixture was stirred for 20 hours under heating conditions of 70 to 80 °C. After cooling the reaction mixture, n-hexane was added, and the n-hexane solution was subjected to post-treatment operations such as normal washing, drying, and concentration, and then purified by silica gel column chromatography to obtain 390 mg (98.5% GC, 100% E, yield 94%) of the target product (E)-3-methylene-7-phenyl-1,6-heptadiene.

[0252] (E)-3-methylene-7-phenyl-1,6-heptadiene [Chemical formula]

[0253] C 14 H 16 Colorless oil. IR (D-ATR): ν = 3083, 3060, 3025, 2929, 2853, 1595, 1496, 1446, 1391, 1307, 1230, 1156, 1069, 991, 963, 896, 742, 692 cm -1 . 1 1H-NMR (500 MHz, CDCl3): δ = 2.38 - 2.48 (4H, m), 5.07 (2H, d-like, J = 7.2 Hz), 5.11 (1H, d-like, J = 11 Hz), 5.29 (1H, d-like, J = 18 Hz), 6.27 (1H, dt, J = 15.8, 6.5 Hz), 6.42 (1H, dd, J = 11, 18 Hz), 6.43 (1H, d-like, J = 15.8 Hz), 7.19 - 7.23 (1H, m), 7.29 - 7.33 (2H, m), 7.35 - 7.38 (2H, m) ppm. 1313C-NMR (125 MHz, CDCl3): δ = 31.09, 31.56, 113.27, 116.07, 125.94, 126.88, 128.46, 130.06, 130.28, 137.72, 138.81, 145.56 ppm. GC-MS (EI, 70 eV): 27, 39, 51, 65, 77, 93, 104, 117 (base peak), 128, 141, 155, 169, 184 (M + ).

Claims

1. The reduction-elimination reaction of the arenesulfonyl group W at the allylic position of the secondary allyl sulfone compound represented by the following general formula (G) and the elimination reaction of hydrogen halide HZ are carried out in this order or in the reverse order to obtain the following general formula (A). 【Chemical 1】 (wherein, R １ , R ２ are each independently a hydrogen atom, or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, W is an arenesulfonyl group, and Z represents a halogen atom.) A process for obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by the formula: 【Chemical 2】 (wherein R １ , R ２ each independently represents a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds.) The process for obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by the following general formula (A), which comprises at least the step of: A process for producing a 2-(3-alkenyl)-1,3-butadiene compound (A), comprising at least the step of:

2. The reduction-elimination reaction of the arenesulfonyl group W at the allylic position of the secondary allyl sulfone compound represented by the following general formula (G) to obtain the following general formula (D). 【Chemical Formula 3】 (In the formula, R １ , R ２ are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms which may contain one or more unsaturated bonds, W is an arenesulfonyl group, and Z represents a halogen atom.) A process for obtaining a halide compound represented by the formula: 【Chemical 4】 (wherein R １ , R ２ are each independently a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms which may contain one or more unsaturated bonds, and Z represents a halogen atom.) The step of obtaining a halide compound (D), The elimination reaction of hydrogen halide HZ of the obtained halide compound (D) to obtain the following general formula (A). 【Chemical Formula 5】 (wherein, R １ , R ２ each independently represents a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds.) A process for obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by the formula: A process for producing a 2-(3-alkenyl)-1,3-butadiene compound (A), comprising at least the step of:

3. The elimination reaction of hydrogen halide HZ of the secondary allyl sulfone compound represented by the following general formula (G) to obtain the following general formula (E). 【Chemical Formula 6】 (In the formula, R １ , R ２ each independently represents a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, W represents an arenesulfonyl group, and Z represents a halogen atom.) A process for obtaining a secondary allyl sulfone compound represented by the formula: 【Chemical Formula 7】 (wherein R １ , R ２ are each independently a hydrogen atom, or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, and W represents an arenesulfonyl group.) The step of obtaining a secondary allyl sulfone compound (E), The reduction-elimination reaction of the arenesulfonyl group W at the allylic position of the obtained secondary allyl sulfone compound (E) to obtain the following general formula (A). 【Chemical 8】 (wherein R １ , R ２ each independently represents a hydrogen atom or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds.) A process for obtaining a 2-(3-alkenyl)-1,3-butadiene compound represented by the formula: A process for producing a 2-(3-alkenyl)-1,3-butadiene compound (A), comprising at least the step of:

4. A secondary allyl sulfone compound represented by the following general formula (G). 【Chemical Formula 9】 (wherein, R １ , R ２ are each independently a hydrogen atom, or a linear, branched or cyclic hydrocarbon group having 1 to 20 carbon atoms and optionally containing one or more unsaturated bonds, W is an arenesulfonyl group, and Z represents a halogen atom.)

5.

6. R １ 、 R ２ wherein one of R and R is a methyl group and the other is a 4-methyl-3-pentenyl group or a methyl group, and the method for producing a 2-(3-alkenyl)-1,3-butadiene compound (A) according to any one of claims 1 to 3.

7. R １ 、 R ２ The secondary allyl sulfone compound according to claim 4, wherein one of R １ and R ２ is a methyl group and the other is a 4-methyl-3-pentenyl group or a methyl group. A halide compound represented by the following general formula (D'). ​ 【Chemical Formula 10】 (wherein one of R １’ , R ２’ is a methyl group, the other is a 4-methyl-3-pentenyl group or a methyl group, and Z represents a halogen atom.) ​

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