JP5366541B2 - Formyltetrahydropyrans, methods for their preparation, and their use in the preparation of liquid crystal compounds - Google Patents

Abstract

The invention relates to formyltetrahydropyrans comprising mesogenic substituents, to a method for the production thereof and to the use thereof for producing substituted tetrahydropyran derivatives.

Description

  The present invention relates to formyltetrahydropyrans having mesogenic substituents, methods for their preparation, and the use of formyltetrahydropyrans for the preparation of substituted tetrahydropyran derivatives.

  Compounds having a tetrahydropyran ring as the central component of the molecule can be used, for example, as components of natural and synthetic fragrances, in drugs or mesogenic or liquid crystal compounds, or as precursors for the synthesis of these substances. It plays an important role in organic chemistry.

  Liquid crystal materials often have 1,4-substituted cyclohexane rings with a generally rod-like structure. When these cyclohexane rings are replaced in any desired direction by 2,5-substituted tetrahydropyran units, the overall physical properties of the molecule can be improved satisfactorily depending on the direction of the electronegative oxygen atom. In particular, an increase in dielectric anisotropy (Δε) can be achieved in both positive (Δε> 0) and negative (Δε <0) dielectric compounds.

  An example in which Δε is positive is described in EP1482019A1 (Patent Document 1). Similarly, in a compound as described in EP0967261A1 (Patent Document 2), it is found that the value of negative Δε increases. Has been. Similarly, the absolute value of [Delta] [epsilon] is thought to decrease via tetrahydropyran units in the opposite direction.

  An increase in positive Δε is advantageous for use in, for example, an IPS (In Plane Switching) type liquid crystal display, and an increase in negative Δε is advantageous in a VA (Vertical Alignment) type liquid crystal display.

  Linear 4-substituted (pseudo-rod, handle or rod-shaped) formylcyclohexanes are useful intermediates for preparing liquid crystal products containing cyclohexane rings. Formyl groups are distinguished by their versatile reactivity, especially in extending the chain to build a carbon skeleton and in the formation of acetal structures. Therefore, a liquid crystal or mesogenic end product with high value is converted into a Wittig reaction (eg, EP0122389A2 (Patent Document 3), DE3509170A1 (Patent Document 4), WO95 / 30723A1 (Patent Document 5) with the aid of formylcyclohexanes). ) Or by condensation of 1,3-dihydroxy compounds (for example, EP0433836A2 (Patent Document 6), DE3306960A1 (Patent Document 7)).

  It has now been found that formyl derivatives are also useful intermediates for the derivatization of tetrahydropyran rings. DE 3306960 A1 (patent document 8) describes a partial structure of formula Ia.

しかしながら、記載される入手方法（例１４）には多数の工程が存在しており、不安定な（ヘミ）アセタール中間体が関与しており、収率が低く再現性がない。加えて、２位にホルミル基を有する物質、５位に更なる置換基を有する物質は当該文献には記載されていない。加えて、現在までの文献は、Ｐ．Ｋｏｃｉｅｎｓｋｉら、Ｓｙｎｔｈｅｓｉｓ（１９９１年）、第１１巻、第１０２９〜３８頁（非特許文献１）で式Ｉｂの１種類の化合物を含むのみである。

However, the described method of acquisition (Example 14) involves a number of steps, involves unstable (hemi) acetal intermediates, and yields are low and not reproducible. In addition, substances having a formyl group at the 2-position and substances having a further substituent at the 5-position are not described in the literature. In addition, the literature to date includes P.I. Kocienski et al., Synthesis (1991), Vol. 11, pp. 1029-38 (Non-Patent Document 1) contain only one compound of formula Ib.

ＤＥ３３０６９６０Ａ１（特許文献９）にはアルデヒド類をアルコール類からの酸化またはカルボン酸類からの還元により調製できる考えが開示されているが、いかなる実施形態においても実施されていない。

DE 3306960 A1 (Patent Document 9) discloses the idea that aldehydes can be prepared by oxidation from alcohols or reduction from carboxylic acids, but is not implemented in any embodiment.

Although only slightly known, it has also been found that certain dihydropyran compounds are suitable as starting materials for the preparation of formyltetrahydropyrans. (2S) -2- (4-fluorohenoxymethyl-3,4-dihydro-2H-pyran is described in MK Gurjar et al., Synthesis (2000), Vol. 4, 557-60 (non-patent literature). To describe known representatives prepared by 2) and having a linear structure, 3- (2-benzyloxyethyl) -3,4-dihydro-2H-pyran was prepared by AP Kozikowski et al. Chem. Soc. Chem. Commun. (1980), 11, 477-9 (Non-Patent Document 3) Simple 2-alkyl or 3 of 3,4-dihydro-2H-pyran Alkyl derivatives have also been described without mention of liquid crystals, to date, for example, C. Fehr et al., Helv. Chim. Acta (1981), 65th. , Pp. 1247-56 from (non-patent document 4), alkyl (alkylene) substituted dihydropyran compound is known.
EP1482019A1 EP0967261A1 EP0122389A2 DE3509170A1 WO95 / 30723A1 EP0433836A2 DE3306960A1 DE3306960A1 DE3306960A1 P. Kocienski et al., Synthesis (1991), Vol. 11, pp. 1029-38. M.M. K. Gurjar et al., Synthesis (2000), Vol. 4, 557-60. A. P. Kozikowski et al. Chem. Soc. Chem. Commun. (1980), Volume 11, Pages 477-9 C. Fehr et al., Helv. Chim. Acta (1981), 65, 1247-56.

  Therefore, it is a further object to increase the method of obtaining linear substituted formyltetrahydropyrans capable of changing the orientation of the pyran ring and to provide a method for their synthesis. The aldehyde formed is inserted into existing and novel syntheses to prepare 2,5-2 substituted tetrahydropyran compounds, whose final products can function, for example, as mesogenic or liquid crystal compounds.

  The object is achieved according to the invention by a process for the preparation of formyltetrahydropyrans of formula II.

（ただし、式ＩＩ中、

(However, in Formula II,

ａ、ｂ、ｃは、互いに独立に、０または１を表し、ただし、ａ＋ｂ＋ｃは、０、１、２または３に等しく、
Ａ^１、Ａ^２、Ａ^３は、互いに独立に、同一または異なって、回転されたものまたは鏡像のものでもよく、

a, b and c, independently of one another, represent 0 or 1, provided that a + b + c is equal to 0, 1, 2 or 3;
A ¹ , A ² , A ³ may be the same or different, independently of each other, rotated or mirror image,

を表し、および
Ｙ^１、Ｙ^２およびＹ^３は、互いに独立に、水素、ハロゲン、ＣＮ、ＮＣＳ、ＳＦ_５、Ｃ_１〜６−アルカニル、Ｃ_２〜６−アルケニル、Ｃ_２〜６−アルキニル、ＯＣ_１〜６−アルカニル、ＯＣ_２〜６−アルケニルまたはＯＣ_２〜６−アルキニルを表し、ただし、脂肪族基は無置換であるか、ハロゲンにより１置換または多置換されており、および
Ｚ^１、Ｚ^２、Ｚ^３は、単結合、１〜６個の炭素原子を有し無置換かＦおよび／またはＣｌで１置換または多置換されているアルキレン橋架け、または−ＣＨ_２Ｏ−、−ＯＣＨ_２−、−（ＣＯ）Ｏ−、−Ｏ（ＣＯ）−、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−ＣＨ_２ＣＨ_２ＣＦ_２Ｏ−または−ＣＦ_２ＯＣＨ_２ＣＨ_２−を表し、
ｎ１は、０、１、２、３または４であり、
ｎ２およびｎ３は、互いに独立に、０、１、２または３であり、
ｎ４は、０、１または２であり、
Ｗ^１は、−ＣＨ_２−、−ＣＦ_２−または−Ｏ−を表し、
Ｒ^１は、Ｈ、ハロゲン、ＣＮ、ＮＣＳ、ＳＦ_５、ＣＦ_３、ＯＣＦ_３、ＮＨ_２、ボロン酸エステル、１〜１５個のＣ原子を有するアルキル基で、該基は無置換であるか、ＣＮにより１置換されているか、ハロゲンにより１置換または多置換されており、ただし加えて、これらの基中の１個以上のＣＨ_２基は、鎖中のヘテロ原子が互いに直接結合しないように、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−（ＣＯ）Ｏ−または−Ｏ（ＣＯ）−で置き換えられていてもよい。)
この方法は、
ａ）式ＩＩＩａ、ＩＩＩｂおよび／またはＩＩＩｃの化合物をヒドロホルミル化するか、

And Y ¹ , Y ² and Y ³ independently of one another are hydrogen, halogen, CN, NCS, SF ₅ , C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, OC _1-6 -alkanyl, OC _2-6 -alkenyl or OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ¹ , Z ² and Z ³ are a single bond, an alkylene bridge having 1 to 6 carbon atoms that is unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH ₂ O—, —OCH _{2 -, - (CO) O} -, - O (CO) -, - CF 2 O -, - OCF 2 -, - CH 2 CH 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted or are either monosubstituted by CN, which is monosubstituted or polysubstituted by halogen, which, in addition, one or more CH ₂ groups in these radicals, as hetero atoms in the chain are not linked directly to one another, -C≡C -, - CH = CH - , - O -, - S -, - SO -, - SO 2 -, - (CO) O- or -O (CO) - may be replaced by. )
This method
a) hydroformylating a compound of formula IIIa, IIIb and / or IIIc,

または
ｂ）少なくとも１つの還元工程を含むＩＶの１つ以上の反応によって、式ＩＶの化合物を反応させるか、

Or b) reacting a compound of formula IV by one or more reactions of IV comprising at least one reduction step,

（ただし、Ｒ^３は、ＣＮ、ＣＯＯＨ、ＣＯＮＨＲ^４、ＣＯＯＲ^４を表し、Ｒ^４は、アルキル、アラルキルまたは（置換されていてもよい）アリールを表す。）
または
ｃ）式Ｖのアルコールを酸化し、式ＩＩのアルデヒドとすること

(However, R ³ represents CN, COOH, CONHR ⁴ , COOR ⁴ , and R ⁴ represents alkyl, aralkyl, or (optionally substituted) aryl.)
Or c) oxidizing an alcohol of formula V to an aldehyde of formula II

（ただし、式ＩＩＩａ〜ｃ、ＩＶおよびＶ中、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃおよびＲ^１は、式ＩＩの意味を有する。）
を特徴とする。
本発明の方法により、容易に入手でき安価な試薬を使用し式ＩＩＩａ〜ｃ、ＩＶまたはＶの中間体より出発して、式ＩＩのテトラヒドロピランアルデヒドを単純な方法で良好な収率により化学的および立体的に高い選択性で入手可能となる。そのアルデヒドは、単独または混合物中で液晶物質として使用できる多数の異なる化合物の合成のための有用な中間体である。そのアルデヒドは、水和物、亜硫酸塩付加物またはアセタールの形でも調製でき、単離でき、精製でき、使用できる。

(However, in Formulas IIIa-c, IV and V, A ¹ , A ² , A ³ , A ⁴ , Z ¹ , Z ² , Z ³ , a, b, c and R ¹ have the meaning of Formula II. .)
It is characterized by.
According to the process of the present invention, starting from an intermediate of formula IIIa-c, IV or V using readily available and inexpensive reagents, the tetrahydropyranaldehyde of formula II is chemically synthesized in good yields in good yield. And sterically high selectivity. The aldehyde is a useful intermediate for the synthesis of a number of different compounds that can be used as liquid crystal materials alone or in a mixture. The aldehyde can also be prepared, isolated, purified and used in the form of a hydrate, sulfite adduct or acetal.

  Thus, the present invention also includes aldehydes of formula II that do not include compounds of the following formula:

  Preferred compounds are described below or follow preferred embodiments in connection with one or more preparation methods or one or more uses of a compound of formula II.

  Independent of each other,

Ｒ^１は、Ｆ、ＯＣＦ_３、ＣＦ_３、ＯＣＦ_２Ｈ、ＳＦ_５を表し、
Ａ^１およびＡ^２は、互いに独立に、１，４−フェニレン、２，５−ジフルオロ−１，４−フェニレンまたは２−フルオロ−１，４−フェニレンを表し、
ａ、ｂは、１に等しく、
ｃは、０に等しく、および／または
Ｚ^１は、単結合、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−（ＣＦ_２）_２−、−ＣＨ_２ＣＦ_２−、−ＣＦ_２ＣＨ_２−、−ＣＨ_２ＣＨ_２ＣＦ_２Ｏ−または−ＯＣＦ_２ＣＨ_２ＣＨ_２−である
ことを特徴とする式ＩＩの化合物の調製が好ましい。

R ¹ represents F, OCF ₃ , CF ₃ , OCF ₂ H, SF ₅ ;
A ¹ and A ² independently of one another represent 1,4-phenylene, 2,5-difluoro-1,4-phenylene or 2-fluoro-1,4-phenylene,
a and b are equal to 1,
c is equal to 0 and / or Z ¹ is a single bond, —CF ₂ O—, —OCF ₂ —, — (CF ₂ ) ₂ —, —CH ₂ CF ₂ —, —CF ₂ CH ₂ —, Preference is given to the preparation of compounds of the formula II, characterized in that they are —CH ₂ CH ₂ CF ₂ O— or —OCF ₂ CH ₂ CH ₂ —.

Similarly,
R ¹ represents F, Cl, Br, boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted, monosubstituted by CN, monosubstituted by halogen, or Polysubstituted, but in addition, one or more of the CH ₂ groups in these groups are —C≡C—, —CH═CH—, —, such that the heteroatoms in the chain are not directly bonded to each other. O—, —S—, —SO—, —SO ₂ —, — (CO) O— or —O (CO) — may be substituted,
A ¹ , A ² and A ³ represent 1,4-phenylene, 2,3-difluoro-1,4-phenylene, 2-fluoro-1,4-phenylene or 3-fluoro-1,4-phenylene, Preference is given to the preparation of compounds of the formula II, characterized in that and a, b and c are independently of each other 0 or 1.

  The preparation of compounds of the formulas A to G is very particularly preferred.

ただし、Ｘ^２は、ＦまたはＯＣＦ_３を表し、およびｇは０、１または２を表し、およびａｌｋｙｌは下に定義される通りである。

Where X ² represents F or OCF ₃ , and g represents 0, 1 or 2, and alkyl is as defined below.

  Corresponding to the preferred preparation methods, suitable starting materials are used in variants a), b) and c).

In a first embodiment (a) of the invention, tetrahydropyranaldehyde II is formed from dihydropyran of formula IIIa-c. In a preferred embodiment of (a), the conversion to aldehyde is performed by a hydroformylation reaction, preferably catalytic hydroformylation using a gas mixture comprising hydrogen and carbon monoxide. In other embodiments, hydrosilane is used in place of hydrogen, and the silylenol ether formed can be readily converted to the corresponding aldehyde. In a preferred embodiment, transition metal catalysts suitable for hydroformylation are used, in particular catalysts of the transition metals rhodium (Rh), ruthenium (Ru) or cobalt (Co). Various ligands can be provided on the metal core of the catalyst on the central metal of the transition metal, such as CO (Brennstoffchemie (1966), 47, 207), phosphine (J. Organomet. Chem. (1977), 124, 85), phosphine oxide (J. Chem. Soc. Chem. Commun. (1994), 115; J. Organomet. Chem. (1995), 488, C20-C22) and phosphorous acid (J. Organomet. Chem). (1991), 421, 121; (1993), 451, C15-C17). Particularly preferred catalysts are cobalt compounds having a carbonyl ligand or rhodium compounds having a phosphorus-containing ligand. Appropriate commercially available (precursor) salts can be treated to form the catalyst in situ in the reaction mixture, eg, in the case of these salts, together with the corresponding ligand, Rh (I ) Acac (CO) ₂ (acac is acetylacetonate), Rh (I) acac (COD) (COD is 1,5-cyclooctadiene), [RhCl (COD)] ₂ or [RhCl (CO) ₂ ] ₂ Rh (I) salt (Strem catalog No. 20, Strem Chemicals, Kehl, Germany), for example, 2 to 10 times molar amount of triphenylphosphine or tris phosphite (ortho-t- Butylphenyl). Specific embodiments of the two-phase or multiphase catalysts known from the literature (Angew. Chemie (1993), 105, 1588) can also be used for the hydroformylation reaction. Thus, dihydropyrans of formula IIIa-c having hydrophilic substituents such as OH, NH ₂ , COOH, SO ₃ H can be converted to HRh (CO) (tppts) ₃ (tppts is triphenylphosphine tris-m-sulfate. In the presence of a sodium salt) in a two-phase system of aqueous / organic phase. Hydroformylation of lipophilic starting materials of formula IIIa-c can be carried out effectively, for example, using so-called SAP catalysts, which consist of a granular, porous support material with a large internal surface area, Above the catalyst complex is distributed or adsorbed like a thin film. This type of support-fixed catalyst system is preferably prepared using HRh (CO) (tppts) ₃ or Co ₂ (CO) ₆ (tppts) ₂ and used for hydroformylation.

  The process for the hydroformylation of the substrate II is characterized in particular by carrying out a catalytic reaction using a rhodium or cobalt transition metal complex of a metal, the complex having a cobalt compound having a carbonyl group or a phosphorus containing ligand. Consists of rhodium compounds.

  When using Rh complexes with dicobalt octacarbonyl or P ligands such as tris (ortho-tert-butylphenyl) phosphite or triphenylphosphine as catalysts, compounds IIIa and IIIc are of the formula Hydroformylated to the corresponding aldehyde of II. However, the regioselectivity of the hydroformylation from compound IIIb to the corresponding aldehyde II is insufficient. Even at relatively low temperatures (40-60 ° C.) and low molar ligand ratios on Rh catalysts (2-4 times over phosphite or phosphine), a ratio position of virtually 1: 1 Isomers are obtained (A. Polo et al., J. Chem. Soc., Chem. Commun. 1990, 600). Therefore, hydroformylation of derivatives IIIa or IIIc, especially IIIa, is preferred.

In a second embodiment (b) of the invention, tetrahydropyranaldehyde II is prepared from a carboxylic acid derivative IV and usable starting materials are in particular free carboxylic acids, carboxylic esters, amides or nitrites or in this position. Other compounds with carbon atoms in the same oxidation state (+ III). In this embodiment, starting materials of the nitrile and alkyl ester type, very particularly R ³ represents CN or —C (O) O-alkyl, this time alkyl in particular methyl, ethyl, isopropyl, t-butyl or Particular preference is given to processes using compounds of the formula III which are benzyl groups. In a preferred embodiment (b), the compound of formula IV is reduced with reduced metals, metal hydrides, alkyl metal compounds or low valent boron compounds to avoid further reduction of the aldehyde to an alcohol. Particularly preferred are metal hydrides and / or boron hydrides, which may further have an alkyl, amino, halogen or alkoxy group. In a particularly preferred embodiment, e.g. Winterfeldt, Synthesis (1975), as described in the literature cited 9,617～630 and therein, a method for reducing the aldehydes, diisobutylaluminum hydride (DIBAL-H) or LiAlH _{(NH 2)} 2 And other dialkylaluminum hydrides or amino hydrides or alkoxy-substituted lithium aluminums, such as LiAlH (Ot-Bu) ₃ . The principle of this method is known. It is found as an example and reference in standard works such as March, Advanced Organic Chemistry, 4th edition, Wiley, New York (1992).

In a third embodiment (c), an alcohol compound of formula V is oxidized to an aldehyde of formula II with an oxidizing agent. In a preferred variant of this process, the oxidation is carried out by an oxidation process which avoids excessive oxidation to carboxylic acids or carboxylic esters, in particular CrO ₃ or chromate (VI) (especially pyridinium chromate). ), Periodinane-type organic iodine reagents (Dess-Martin method), DMSO / DCC (Pfitzner-Moffatt oxidation), DMSO / oxalyl dichloride (Swern oxidation), acetone / Al (O-alkyl) ₃ (Openopener oxidation) or NaOCl (catalyzed with N-oxidized 2,2,6,6-tetramethylpiperidine (TEMPO) or transition metal catalysts). As representatives of known specialist literature of the type of reaction already mentioned, the following documents are cited.

CrO ₃ oxidation: (a) J. Org. C. Sauer, “Organic Synthesis”, John Wiley Sons, New York (1963), Coll. Vol. 4, 813; b) G.G. R. Rasmusson et al., (1973), Coll. Vol. 5, 324; c) R.I. W. Ratcliffe; ibid (1988), Coll. Vol. 6, 373; d) J. et al. C. Collins, W.M. W. Hess, ibid (1988), Coll. Vol. 6, 644; e) B.E. Khadilkar et al., Synth. Commun. (1996), 26, 205.

  Dess-Martin oxidation: a) B. Dess, J.M. C. Martin, J.M. Org. Chem. (1983) 48, 4155; Amer. Chem. Soc. (1991) 113, 7277; Speicher et al. Pract. Chem. (1996) 338, 588.

  Pfitzner-Moffatt oxidation: G. Moffat, “Oxidation”, Vol. 2, R.D. L. Augustine and D.C. J. et al. Trecker-Marcel Dekker, New York, 1971, 1-64 (using DMSO / DCC).

  Swern oxidation: a) A. K. Sharma, D .; Swern, Tetrahedron Lett. (1974), 1503; Swern et al. Org. Chem. (1976) 41, 3329; c) P.I. Kocienski, R.A. Whitby, Synthesis (1991) 1029.

  Openauer oxidation: C.I. Djerassi, “Organic Reactions”, John Wiley Sons, New York (1951), Vol. 6, 207.

  NaOCl oxidation, catalyzed by Ru or TEMPO: a) R.I. J. et al. Crawford, J.M. Org. Chem. (1983) 48, 1367; L. Anelli et al., Org. Synth. (1990) 69, 212.

  The Swern oxidation of the corresponding carbinol described in Kocienski et al. Serves as a reference for 2-formyltetrahydropyran.

Alcohol compound V is generally prepared from nitriles and carboxylic acid derivatives of formula IV by reduction from standard methods. A strong reducing agent such as LiAlH ₄ can be used for this purpose.

  The invention further relates to the preparation of 2- or 3-substituted dihydropyran compounds of the formulas IIIa-c, in particular IIIb and IIIc, which can be prepared in a surprisingly simpler way than the corresponding homoallylic alcohol via the intermediate ( Schemes 1-3).

  The novel compounds of formula IIIb and IIIc are part of the present invention. The 2-substituted dihydropyrans known to date are C.I. Fehr et al., Helv. Chim. Acta (1981) 65, 1247-56 and alkyl (alkylene) substituted dihydropyrans and M.I. K. Prepared without mention of liquid crystal compounds with compounds of the following formula according to Gurjar et al., Synthesis (2000), 4, 557-60.

現在までに既知の３−置換ジヒドロピランは、例えばＰ．Ｋｏｃｉｅｎｓｋｉら、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．（１９８５）、１８７９〜８４によるアルキル置換ジヒドロピランである。

To date, 3-substituted dihydropyrans known are e.g. Kocienski et al. Chem. Soc. Perkin Trans. (1985), 1879-84, alkyl-substituted dihydropyrans.

  The compounds of formula IIIb and IIIc of the present invention are characterized below.

ａ、ｂ、ｃが同時に０の場合、
Ｒ^１は、ハロゲン、ＣＮ、ＮＣＳ、ＳＦ_５、ＣＦ_３、ＯＣＦ_３、ＮＨ_２、１〜１５個のＣ原子を有するアルキル基で、該基はＣＮにより１置換されているか、ハロゲンにより１置換または多置換されており、ただし加えて、これらの基中の１個以上のＣＨ_２基は、鎖中のヘテロ原子が互いに直接結合しないように、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−ＣＯＯ−または−ＯＣＯ−で置き換えられていてもよく、および
ＩＩＩｂでａ＝１およびｂ＋ｃ＝０およびＡ^１が１，４−フェニレンに等しい場合、
Ｚ^１は−ＯＣＨ_２−および−ＣＨ_２ＣＨ_２−に等しくない。

When a, b and c are 0 at the same time,
R ¹ is halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , an alkyl group having 1 to 15 C atoms, and the group is 1-substituted by CN or 1-substituted by halogen Or are polysubstituted, but in addition one or more of the CH ₂ groups in these groups are —C≡C—, —CH═CH—, so that the heteroatoms in the chain are not directly bonded to each other. -O -, - S -, - SO -, - SO 2 -, - COO- or -OCO- may be replaced by, and IIIb a = 1 and b + c = 0 and ^{A 1} is 1,4 If equal to phenylene,
Z ¹ is not equal to —OCH ₂ — and —CH ₂ CH ₂ —.

a is preferably 1, 2 or 3. When a is 0, R ¹ preferably represents an alkyl group having 1 to 15 C atoms, which group is mono- or polysubstituted by fluorine, but in addition, in these groups One or more CH ₂ groups may be —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, so that heteroatoms in the chain are not directly bonded to each other. , -COO- or -OCO-.

  In a first variant of the preparation of dihydropyran compounds of formula IIIa-c, a 1-substituted homoallyl alcohol is allylated at the free OH group and a ring-opened diene compound by ring-closing olefin metathesis leaving the ethylene molecule Is converted to 2-substituted 3,6-dihydro-2H-pyran. In a preferred embodiment shown in Scheme 1, 2-substituted dihydropyran IIIa is obtained by a synthetic method in which intermediate VII is obtained from homoallylic alcohol of formula VI by O-allylation. Olefin ring-closing metathesis is preferably performed by a ruthenium-methylidene catalyst with a carbene or phosphine ligand (eg, by various “Grubbs catalysts” described by Grubbs et al.), Or by a new and improved variant. .

  Allylation of VI is carried out, for example, in micellar catalysis using allyl halide in the presence of cetyltrimethylammonium bromide in tetrahydrofuran and a little water (B. Jursic et al., Tetrahedron (1988). 44, 6777).

反応手順の第２の変法では、１−置換ホモアリルアルコールは、一般にヒドロホルミル化され、それからかまたは同時にヘミアセタールの形成により閉環される。類似して、得られるＯＨ置換テトラヒドロピランからＯＨ基を隣接するプロトンと共に脱離することで、必要とされる２−置換３，６−ジヒドロ−２Ｈ−ピラン誘導体が得られる。好ましい実施形態では、式ＶＩのホモアリルアルコールが使用され、スキーム２に示されるようにジヒドロピランＩＩＩｂの２−置換誘導体がヒドロホルミル化、ヘミアセタールの形成および生成されるＯＨ基の脱離後に得られる。ＯＨ基は水としてか、脱離基、特に好ましくはメタンスルホン酸エステルまたはｐ−トルエンスルホン酸エステルに変換後に脱離される

In a second variation of the reaction procedure, the 1-substituted homoallyl alcohol is generally hydroformylated and then or simultaneously closed by the formation of a hemiacetal. Similarly, the required 2-substituted 3,6-dihydro-2H-pyran derivative is obtained by eliminating the OH group with the adjacent proton from the resulting OH-substituted tetrahydropyran. In a preferred embodiment, a homoallylic alcohol of formula VI is used and a 2-substituted derivative of dihydropyran IIIb is obtained after hydroformylation, formation of a hemiacetal and elimination of the resulting OH group as shown in Scheme 2. . The OH group is eliminated after conversion to water or as a leaving group, particularly preferably methanesulfonic acid ester or p-toluenesulfonic acid ester

スキーム２で示される２つの反応工程は、引き続いてかまたは組み合わされた反応順序で行われる。ヒドロホルミル化は原理的に文献から知られる方法に従い、具体的にはＷｕｔｓら（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．（１９８４）、２５、４０５１〜４）に基づく実験室的な合成である。使用されるロジウム触媒である酢酸ロジウム二量体は良好な選択性を有し、取り扱いが容易である。原理的には、容易に入手できる酢酸ロジウムの代わりに、他の商業的なロジウム触媒または文献より既知の有機金属コバルト触媒、特にコバルトカルボニルも使用できる。

The two reaction steps shown in Scheme 2 are performed sequentially or in a combined reaction sequence. Hydroformylation is in principle a laboratory synthesis based on methods known from the literature, specifically based on Wuts et al. (Tetrahedron Lett. (1984), 25, 4051-4). The rhodium acetate dimer, which is the rhodium catalyst used, has good selectivity and is easy to handle. In principle, instead of the readily available rhodium acetate, other commercial rhodium catalysts or organometallic cobalt catalysts known from the literature, in particular cobalt carbonyl, can also be used.

  In a third variant of the preparation of dihydropyran, a 2-substituted homoallyl alcohol of formula XII is hydroformylated and cyclized to give a compound of formula XIII. Subsequent elimination of the OH group on XIII yields 3-substituted 3,4-dihydro-2H-pyran of formula IIIc (Scheme 3).

スキーム２に従う２−置換物質ＶＩに対する同じコメントを、同時閉環を伴うヒドロホルミル化に適用する。

The same comments for 2-substituted material VI according to Scheme 2 apply to hydroformylation with simultaneous ring closure.

  Removal of the OH group in compounds X and XIII to yield elimination products IIIb and IIIc is similar to that of Boeckman et al. (J. Am. Chem. Soc. (1991), 113, 5337-53, Scheme 3). Each is done by separation. For this purpose, for example, mesyl chloride and triethylamine are used to mesylate the OH group, which is then removed by gentle warming. Similarly, p-toluenesulfonyl chloride is suitable for forming the leaving group.

  Particular preference is given to a process for preparing a compound of formula II from a compound of formula IIIb or IIIc. The method is characterized in that the compound of formula IIIb or IIIc can be prepared from the following compound of formula X or XIII, respectively, after directly removing the hydroxyl group or converting it to a leaving group.

ただし、Ａ^１、Ａ^２、Ａ^３、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃおよびＲ^１は、式ＩＩと同じ意味を有する。

However, A ¹ , A ² , A ³ , Z ¹ , Z ² , Z ³ , a, b, c and R ¹ have the same meaning as in Formula II.

  In a preferred procedure, compounds of formula X and XIII are prepared from compounds of formula VI and XII, respectively, by a hydroformylation step or ring closure.

ただし、Ａ^１、Ａ^２、Ａ^３、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃおよびＲ^１は、式ＩＩと同じ意味を有する。

However, A ¹ , A ² , A ³ , Z ¹ , Z ² , Z ³ , a, b, c and R ¹ have the same meaning as in Formula II.

  The homoallylic alcohols of the formulas VI and XII are known from the prior art and are commercially available or can themselves be easily prepared by synthetic methods known from the literature.

  Scheme 4 shows the synthesis of 1-substituted homoallyl alcohols from aldehydes. In this synthesis, for example, an allyl-Grignard reagent is reacted with an aldehyde. In this case, the aldehyde is a known compound or is obtained, for example, by a method based on the method of the invention.

スキーム５は、式ＸＶＩのハロゲン化アリル誘導体より出発してホモアリルアルコールの２−置換誘導体の合成経路の概要を示す。

Scheme 5 outlines a synthetic route for 2-substituted derivatives of homoallyl alcohol starting from an allyl halide derivative of formula XVI.

例えばアルデヒドＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−［Ａ^３−Ｚ^３］_ｃ−ＣＨＯより出発して、例えばＲｅｆｏｒｍａｔｓｋｙ合成により不飽和エステルＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−［Ａ^３−Ｚ^３］_ｃ−ＣＨ＝ＣＨ−ＣＯ_２−アルカニルを得て、引き続きＤＩＢＡＬ−Ｈを使用して対応するアリルアルコールＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−［Ａ^３−Ｚ^３］_ｃ−ＣＨ＝ＣＨ−ＣＨ_２ＯＨ還元し、最後にＰＢｒ_３（Ｈａｌ＝Ｂｒ）、ＰＣｌ_５またはＳＯ_２Ｃｌ_２（Ｈａｌ＝Ｃｌ）またはＨＩ（Ｈａｌ＝Ｉ）を使用するハロゲン化より調製される式ＸＶＩより出発して、適当な金属または有機金属試薬との反応により化合物ＸＶＩＩを得るが、ここで「Ｍｅｔ」はＣｕ、Ｂｉ（ｒａｄｉｃａｌ）_２、Ｉｎ（ｒａｄｉｃａｌ）_２、Ｓｎ（ｒａｄｉｃａｌ）_３、Ｓｎ（ｒａｄｉｃａｌ）、Ｚｎ（ｒａｄｉｃａｌ）、Ｇｅ（ｒａｄｉｃａｌ）を表し、使用される金属または有機金属試薬に依存して、「ｒａｄｉｃａｌ」は１種類以上の有機基、配位子または該金属上の対イオンを表す。中間体として形成されたＸＶＩＩを先立って単離することなく行うこともできる更なる反応ＸＶＩＩによりホルムアルデヒド（または合成上同等のもの）より、対応する作業の後に式ＸＩＩの所望のホモアリルアルコールを得る。

For example, starting from aldehyde R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b- [A ³ -Z ³ ] _c -CHO, for example, unsaturated ester R ^1- [A by Reformatsky synthesis _{^{1 -Z 1] a - [a}} 2 -Z 2] b - [a 3 -Z 3] c -CH = CH-CO 2 - Newsletter alkanyl, subsequently allyl alcohol R corresponding using DIBAL-H _{^{1 - [a 1 -Z 1]}} a - [a 2 -Z 2] b - [a 3 -Z 3] c -CH = CH-CH 2 and OH reduced, finally _{PBr 3 (Hal = Br),} PCl Starting from Formula XVI prepared by halogenation using ₅ or SO ₂ Cl ₂ (Hal = Cl) or HI (Hal = I), compound XVII is obtained by reaction with a suitable metal or organometallic reagent. ,here Met "is _{Cu, Bi (radical) 2,} In (radical) 2, Sn (radical) 3, Sn (radical), Zn (radical), represents the Ge (radical), depending on the metal or organometallic reagents used Thus, “radical” represents one or more organic groups, ligands or counterions on the metal. Further reaction XVII, which can also be carried out without prior isolation of XVII formed as an intermediate, yields the desired homoallylic alcohol of formula XII from formaldehyde (or a synthetic equivalent) after the corresponding work. .

  Further availability of the homoallylic alcohol of formula XII can be achieved as shown in Scheme 6. Here, “Hal” has the same meaning as above in Scheme 5 and “Met” is preferably Cu (see A. Carpita, R. Rossi, Synthesis (1982), 469).

ハロゲン化物ＸＶＩＩＩは、−スキーム４中の方法に対応するやり方で−適当な試薬を使用して有機金属誘導体ＸＩＸに転化され、引き続きＸＸと反応させて酢酸ホモアリルＸＸＩを得る。そして、式ＸＩＩの所望のホモアリルアルコールは、ＸＸＩから鹸化によって入手可能である。

The halide XVIII is converted to the organometallic derivative XIX using a suitable reagent in a manner corresponding to the method in Scheme 4, followed by reaction with XX to give homoallyl acetate XXI. And the desired homoallylic alcohol of formula XII is available from XXI by saponification.

Furthermore, the homoallyl alcohol of formula XII in which R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b- [A ³ -Z ³ ] _c represents an alkyl group is also an alkyl of the dianion of crotonic acid Corresponding alkyl using chloride R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b- [A ³ -Z ³ ] _c -Hal or obtained by subsequent reduction using LiAlH ₄ it can. This dianion is obtained, for example, from crotonic acid by reaction with two equivalents of lithium diisopropylamide (LDA) (PE Pfeffer, LS Silbert, J. Org. Chem. (1971), 36, 3290). R. H. van der Veen, H. Surfatain, J. Org. Chem. (1985), 50, 342).

Synthesis of carboxylic acid derivatives of formula IV for reduction to aldehydes is performed as outlined with reference to the general examples in Schemes 7 and 8. Here, as in formula IV, MES represents the mesogenic group R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b- [A ³ -Z ³ ] _c- . The ester group can also be replaced with a substituent represented by R ³ in Formula IV. In both examples, compounds of formula IV (represented by representative examples of compounds XXIV and XXVII) can be prepared by hydrogenating ring-closing metathesis and subsequent metathesis products from the corresponding substituted precursors of formula XXII or XXV. can get. Precursors of formula XXII and XXV are obtained as described in EP1482019A1 for these or similar diene compounds. On the other hand, the compound of formula XXII is obtained by alkylation of allyl alcohol _{HO-CH (MES) -CH 2} CH = CH 2 by using the corresponding acrylate compounds.

式ＩＶ（Ｒ^３＝ＣＮ）のシアノ−置換の代表例は、例えば、ジヒドロピランＩＩＩｃを経由して間接的に入手可能である。これらはガス状塩酸を使用し無置換５，６−ジヒドロ−４Ｈ−ピランの塩素化に類似して塩素化でき、そしてＡｇＣＮ（Ｂ．Ａ．Ｎｅｌｓｏｎら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．（１９５６）、２１、７９８）を使用するか、ＳｎＣｌ_２存在下にトリメチルシリルシアニド（Ｍ．Ｒｅｅｔｚら、Ｔｅｔｒａｈｅｄｒｏｎ（１９８３）、３３、９６１）により、式ＩＶのシアノ化合物に変換できる。

A representative example of a cyano-substitution of formula IV (R ³ = CN) is available indirectly, for example via dihydropyran IIIc. These can be chlorinated using gaseous hydrochloric acid analogously to the chlorination of unsubstituted 5,6-dihydro-4H-pyran, and AgCN (BA Nelson et al., J. Org. Chem. (1956), 21, 798) or by trimethylsilylcyanide (M. Reetz et al., Tetrahedron (1983), 33, 961) in the presence of SnCl ₂ can be converted to a cyano compound of formula IV.

  Thus, a compound of formula IV, specifically intended to be reduced to a compound of formula II, is prepared by hydrogenation of a dihydropyran derivative, which in turn is a catalyst with elimination of ethylene from a suitably substituted diene. Preference is given to a process for the preparation of tetrahydropyran-aldehydes of the formula II, characterized in that they are prepared by mechanical ring-closing metathesis.

  Tetrahydropyran-aldehydes of formula II can be used to prepare further mesogenic or liquid crystalline tetrahydropyran derivatives. Aldehyde compound II is preferably used for the addition of aldehyde groups or the synthesis of condensation products to build partial structures of mesogenic structures. Aldehyde groups are particularly preferably used for building 5-6 membered ring systems, very particularly for building further tetrahydropyran or 1,3-dioxane rings.

Accordingly, a preferred use of the aldehyde of formula II is characterized in that the reaction is carried out with 1,3-diol to obtain dioxane. This is done in a manner known per se, as described in the literature (for example, Houben-Weyl, Methoden der organicis Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag chemistry, Storg, Standard work). The 1,3-diol is preferably substituted in the 2-position by a simple or mesogenic group such as R ¹ (defined as in Formula II). Particular preference is given to a group such as R ¹ or a substitution by the group —A—R ¹ , wherein A represents cyclohexane-1,4-diyl, tetrahydropyran-2,5-diyl or 1,3-dioxane-2,5-diyl. Represent.

  A further preferred use of the aldehyde of formula II is characterized in that the reaction is carried out with an allyl metal compound to obtain homoallyl alcohol as a precursor of tetrahydropyran. The homoallylic compound formed serves as starting material for the preparation of further adjacent pyran rings by the methods already described above (Schemes 1 and 2).

  Also preferably, the aldehyde group in the aldehyde compound of formula II is used for chain extension by the Wittig reaction, resulting in the formation of a 1,2-ethenylene bridge on tetrahydropyran. Thus, the use of an aldehyde compound of formula II is particularly characterized in that the compound of formula IX is prepared from aldehyde II by a Wittig reaction.

ただし、
Ｒ^１、Ｒ^２、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃは、式ＩＩの意味を有し、および、それぞれの場合で互いに独立に、
Ａ^５、Ａ^６は、Ａ^１に定義される通りであり、
Ｚ^５、Ｚ^６は、Ｚ^１に定義される通りであり、および
ｅおよびｆは、ａに定義される通りである。

However,
R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , Z ¹ , Z ² , Z ³ , a, b, c have the meaning of formula II and are independent of each other in each case In addition,
A ⁵ and A ⁶ are as defined in A ¹ ,
Z ⁵ and Z ⁶ are as defined for Z ¹ , and e and f are as defined for a.

  In a further preferred form of use of the compound of formula II, the hydropyran ring substituted with an optionally substituted ethenyl group is an aldehyde to allylation of a carbonyl function, etherification of an alcohol using a propynyl group and subsequent enyne. Prepared by metathesis (see EP1482020A1). The optional substitution here depends on the optional substitution of the aryl-Grignard compound used in the allylation. Thus, in this case, the use of an aldehyde compound of formula II is notably used as a precursor for the synthesis of Qa compounds of formula Qa, (partially) saturated hydrogenation products of compounds of formula Qa or Qa of formula Qb or Qc. It is characterized by preparing a body.

ただし、Ｑａ、ＱｂおよびＱｃ中において、
Ｒ^１、Ｒ^２、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃは、式ＩＩの意味を有し、および、それぞれの場合で互いに独立に、
Ａ^５、Ａ^６は、Ａ^１に定義される通りであり、
Ｚ^５、Ｚ^６は、Ｚ^１に定義される通りであり、および
ｅおよびｆは、式ＩＩ中のａに定義される通りである。

However, in Qa, Qb and Qc,
R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , Z ¹ , Z ² , Z ³ , a, b, c have the meaning of formula II and are independent of each other in each case In addition,
A ⁵ and A ⁶ are as defined in A ¹ ,
Z ⁵ , Z ⁶ are as defined for Z ¹ , and e and f are as defined for a in Formula II.

  A4 in Qa, Qb and Qc is preferably a ring of the following formula.

この場合、

in this case,

Ｒ^１は、Ｆ、ＯＣＦ_３、ＣＦ_３、ＯＣＦ_２Ｈ、ＣＮ、ＳＦ_５を表し、
Ａ^１およびＡ^２は、互いに独立に、１，４−フェニレン、２，５−ジフルオロ−１，４−フェニレンまたは２−フルオロ−１，４−フェニレンを表し、
ａ、ｂは、１に等しく、
ｃは、０に等しく、および
Ｚ^１は、単結合、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−（ＣＦ_２）_２−、−ＣＨ_２ＣＦ_２−、−ＣＦ_２ＣＨ_２−、−ＣＨ_２ＣＨ_２ＣＦ_２Ｏ−または−ＯＣＦ_２ＣＨ_２ＣＨ_２−
である式ＩＩの化合物の使用が好ましい。

R ¹ represents F, OCF ₃ , CF ₃ , OCF ₂ H, CN, SF ₅ ;
A ¹ and A ² independently of one another represent 1,4-phenylene, 2,5-difluoro-1,4-phenylene or 2-fluoro-1,4-phenylene,
a and b are equal to 1,
c is equal to 0, and Z ¹ is a single bond, —CF ₂ O—, —OCF ₂ —, — (CF ₂ ) ₂ —, —CH ₂ CF ₂ —, —CF ₂ CH ₂ —, —CH ₂ CH ₂ CF ₂ O— or —OCF ₂ CH ₂ CH ₂ —
Preference is given to the use of compounds of the formula II

Similarly,
R ¹ is F, Cl, Br, a boronic acid ester or an alkyl group having 1 to 15 C atoms, and the group is unsubstituted, monosubstituted by CN, monosubstituted or polysubstituted by halogen. Substituted, but in addition, one or more of the CH ₂ groups in these groups is —C≡C—, —CH═CH—, —O, so that the heteroatoms in the chain are not directly bonded to each other. -, - S -, - SO -, - SO 2 -, - (CO) O- or -O (CO) - a, may be replaced independently of one another, and a ^{1, a 2} and ^{a 3} 1,4-phenylene, 2,3-difluoro-1,4-phenylene, 2-fluoro-1,4-phenylene or 3-fluoro-1,4-phenylene, and a, b and c are independently of each other , 0 or 1 of the formula II The use of compounds is preferred.

  The use of tetrahydropyranaldehydes of the following formulas A to G is particularly preferred.

ただし、Ｘ^２はＦまたはＯＣＦ_３を表しており、ａｌｋｙｌは一般に以下に定義される通りである。特に、式Ａ〜Ｇ中のａｌｋｙｌは直鎖で飽和または不飽和の１〜８個のＣ原子を有する炭素鎖を表す。

Where X ² represents F or OCF ₃ and alkyl is generally as defined below. In particular, alkyl in formulas A to G represents a straight chain, saturated or unsaturated carbon chain having 1 to 8 C atoms.

  The above process for preparing aldehydes of formula II of the present invention and the use thereof, as a whole, 2,5-2 substituted tetrapyran derivatives, in particular the formula

を調製する途が開かれ、
ａ）上の方法の１つ以上でホルミルテトラヒドロピランを調製することと、および
ｂ）２，５−２置換テトラヒドロピラン誘導体を調製するために、本発明の上の実施形態の１つ以上によりホルミルテトラヒドロピランを使用することと
を含み、
ただし、
Ｒ^１、Ｒ^２、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ｚ^１、Ｚ^２、Ｚ^３、ａ、ｂ、ｃは、式ＩＩの意味を有し、および、それぞれの場合で互いに独立に、
Ａ^５、Ａ^６は、Ａ^１に定義される通りであり、
Ｚ^５、Ｚ^６は、Ｚ^１に定義される通りであり、および
ｆは、０、１または２であり、および
ｅは、式ＩＩ中でａに定義される通りである。方法経路に依存して、パラメータの意味はその中で規定される制限に従うか、そこより直接的に明らかである。

The way to prepare
a) preparing formyltetrahydropyran by one or more of the above methods; and b) formyl according to one or more of the above embodiments of the present invention to prepare 2,5-2 substituted tetrahydropyran derivatives. Using tetrahydropyran,
However,
R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , Z ¹ , Z ² , Z ³ , a, b, c have the meaning of formula II and are independent of each other in each case In addition,
A ⁵ and A ⁶ are as defined in A ¹ ,
Z ⁵ , Z ⁶ are as defined for Z ¹ , and f is 0, 1 or 2, and e is as defined for a in Formula II. Depending on the method path, the meaning of the parameters obeys the restrictions specified therein or is more directly apparent.

  A further use of aldehydes of formula II is derivatization as formation of hydrates or sulfite adducts or acetals for purification methods, or as protection of aldehydes during purification, chemical reaction or storage.

A further aspect of the invention comprises a novel formyltetrahydropyran of formula II as defined above, preferably, independently of one another, at least one of Z ¹ , Z ² , Z ^{3 in} the molecule is — _{CF 2 CF 2 -, - CF} 2 CH 2 -, - CH 2 CF 2 -, - CH 2 CH 2 CF 2 O -, - OCF 2 CH 2 CH 2 -, - CF 2 O- or -OCF ₂ - group Or R ¹ corresponds to NCS, SF ₅ , CF ₃ , OCF ₃ or OCHF ₂ , or

ことを特徴とする。

It is characterized by that.

  Particular preference is given to aldehydes of the formulas IIa, IIb and IIc.

ただし、
Ｒ^１１およびＲ^１２は、Ｆ、ＣＦ_３、ＯＣＦ_３、ＣＮ、ＮＣＳ、ＳＦ_５または１〜１５個のＣ原子を有するアルキル基で、該基はハロゲンにより１置換または多置換されており、ただし加えて、これらの基中の１個以上のＣＨ_２基は、鎖中のヘテロ原子が互いに直接結合しないように、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−（ＣＯ）Ｏ−または−Ｏ（ＣＯ）−で置き換えられていてもよく、
Ｒ^１３は、式ＩＩ中のＲ^１で定義される通りであり、
Ｌ^１、Ｌ^２は、それぞれ独立に、Ｈ、ＣｌまたはＦに等しく、および
Ａ^１、Ａ^２、Ｚ^１、Ｚ^２、ａ、ｂは、式ＩＩ中の通りの定義を有する。

However,
R ¹¹ and R ¹² are F, CF ₃ , OCF ₃ , CN, NCS, SF ₅ or an alkyl group having 1 to 15 C atoms, the group being mono- or polysubstituted by halogen, provided that In addition, one or more CH ₂ groups in these groups may be —C≡C—, —CH═CH—, —O—, —S—, so that heteroatoms in the chain are not directly bonded to each other. _{-SO -, - SO 2 -,} - (CO) O- or -O (CO) - may be replaced by,
R ¹³ is as defined for R ¹ in Formula II;
L ¹ , L ² are each independently equal to H, Cl or F, and A ¹ , A ² , Z ¹ , Z ² , a, b have the definitions as in Formula II.

  Very particular preference is given to formyltetrahydropyran of the above formulas A, B, C, D, E, F and G.

In the context of the present invention, the term "alkyl"-unless otherwise defined in the description or claims--in its most general sense, is linear or branched, saturated or unsaturated. Saturated aliphatic hydrocarbon having 1 to 15 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms A group which is unsubstituted or mono- or polysubstituted with fluorine, chlorine, bromine, iodine, carboxyl, nitro, NH ₂ , N (alkanyl) ₂ and / or cyano, provided that it is the same or different substitution It may be polysubstituted by groups. The alkyl group in the aliphatic hydrocarbon chain may itself be functionalized.

When the alkyl group is saturated, it is also called “alkanyl”. Furthermore, the term “alkyl” also includes hydrocarbon groups which are unsubstituted or correspondingly the same or different, in particular mono- or polysubstituted by F, Cl, Br, I and / or CN, one or more CH ₂ groups, as hetero atoms in the chain (O or S) are not linked directly to one another, -O- ( "alkoxy", "oxaalkyl"), - S- ( "thioalkyl"), —SO ₂ —, —CH═CH — (“alkenyl”), —C≡C — (“alkynyl”), — (CO) O— or —O (CO) — may be substituted. Preferably, alkyl is a straight or branched, unsubstituted or substituted alkanyl, alkenyl or alkoxy group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Where alkyl represents an alkanyl group, this is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, n- heptyl, n- _{octyl, CF 3, CHF 2, CH} 2 F, CF 2 CF 3. The alkanyl group is particularly preferably straight-chain, unsubstituted or substituted with F.

The term “alkyl” also includes “alkoxy” or “oxaalkyl” groups, as one or more CH ₂ groups in an alkyl group may be replaced by —O—. Alkoxy means an O-alkyl group in which the oxygen atom is substituted by an alkoxy group or directly attached to a substituted ring, where alkyl is as defined above; alkyl is preferably alkanyl Or alkenyl. Preferred alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy and octyloxy, although each of these groups is preferably substituted by one or more fluorine atoms. Particularly preferably, _{alkoxy, OCH 3, OC 2 H 5} , O-n-C 3 H 7, O-n-C 4 H 9, O-t-C 4 H 9, OCF 3, OCHF 2, OCHF , or it is a OCHFCHF _2. In the context of the present invention, the term “oxaalkyl” refers to an alkyl in which at least one non-terminal CH ₂ group is replaced by —O— so that there are no adjacent heteroatoms (O or S). Means group. Preferably, the oxaalkyl comprises a linear group of formula C _a H _{2a + 1} —O— (CH ₂ ) _b —, wherein a and b are each independently 1, 2, 3, 4, 5, 6, Represents 7, 8, 9 or 10, and particularly preferably, a is an integer of 1 to 6 and b is 1 or 2.

A “thioalkyl” group is present when one or more CH ₂ groups in an alkyl group as defined above are replaced by sulfur. “Thioalkyl” preferably comprises a straight chain group of the formula C _a H _{2a + 1} —S— (CH ₂ ) _b —, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9 Or 10 and b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and particularly preferably, a is an integer of 1 to 6 and b is 1 or 2. Similarly, a thioalkyl group may be substituted with F, Cl, Br, I and / or CN, and is preferably unsubstituted.

In the context of the present invention, the term “alkenyl” means an alkyl group as defined above in which one or more —CH═CH— groups are present. If there are two —CH═CH— groups in this group, they can also be referred to as “alkadienyl”. An alkenyl group can contain 2 to 15 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms and can be branched Or it is preferably a straight chain. This group is unsubstituted or identically or differently mono- or polysubstituted, in particular F, Cl, Br, I and / or CN, ie hydrogen of one or both of the —CH═CH— units and A further CH ₂ or CH ₃ group hydrogen of the alkenyl group may be replaced by a corresponding substituent. Furthermore, —O— (“alkenyloxy”), —S—, —C≡C—, so that one or more CH ₂ groups are independent of each other and heteroatoms (O or S) are not directly bonded to each other. -CO-,-(CO) O-, and -O (CO)-may be substituted. When there are other than hydrogen on both carbon atoms of the CH═CH group, for example, when it is not a terminal group, there are two configurations of CH═CH: the E isomer and the Z isomer. The corresponding state applies to C═C double bonds substituted with halogen and / or —CN. In general, the E isomer (trans) is preferred. Preferably, the alkenyl group contains 2, 3, 4, 5, 6 or 7 carbon atoms and is vinyl, allyl, 1E-propenyl, 2-propenyl, 1E-butenyl, 1E-pentenyl, 1E-hexenyl, 1E- Heptenyl, 2-propenyl, 2E-butenyl, 2E-pentenyl, 2E-hexenyl, 2E-heptenyl, 3-butenyl, 3E-pentenyl, 3E-hexenyl, 3E-heptenyl, 4-pentenyl, 4Z-hexenyl, 4E-hexenyl, Mean 4Z-heptenyl, 5-hexenyl or 6-heptenyl. Particularly preferred alkenyl groups are vinyl, allyl, 1E-propenyl, 2-propenyl and 3E-butenyl.

An alkynyl group is present when one or more CH ₂ groups in an alkyl group are replaced with —C≡C—. It is also possible to replace one or more CH ₂ groups with — (CO) O— or —O (CO) —. Preferred groups here are: acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, 2-acetoxyethyl 2-propionyloxyethyl, 2-butyryloxyethyl, 2-acetoxypropyl, 3-propionyloxypropyl, 4-acetoxybutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, methoxycarbonylmethyl, Ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, 2- (methoxycarbonyl) ethyl, 2- (ethoxycarbonyl) ethyl, 2- (propyl Po alkoxycarbonyl) ethyl, 3- (methoxycarbonyl) propyl, 3- (ethoxycarbonyl) propyl and 4- (methoxycarbonyl) butyl.

The CH ₂ group of the alkyl group is replaced with unsubstituted or substituted —CH═CH—, and the adjacent CH ₂ group is replaced with CO, — (CO) O— or —O (CO) —. In this case, this group may be linear or branched. Preferably it is straight-chain and has 4 to 12 C atoms. Therefore, particularly preferred are acryloyloxymethyl, 2-acryloyloxyethyl, 3-acryloyloxypropyl, 4-acryloyloxybutyl, 5-acryloyloxypentyl, 6-acryloyloxyhexyl, 7-acryloyloxyheptyl, 8-acryloyloxy. Octyl, 9-acryloyloxynonyl, methacryloyloxymethyl, 2-methacryloyloxyethyl, 3-methacryloyloxypropyl, 4-methacryloyloxybutyl, 5-methacryloyloxypentyl, 6-methacryloyloxyhexyl, 7- Means methacryloyloxyheptyl or 8-methacryloyloxyoctyl.

  When an alkyl group, alkanyl group, alkenyl group or alkoxy group is replaced by at least one halogen, preferably this group is straight-chain. Halogen is preferably F or Cl. In the case of polysubstitution, preferably the halogen is F. The resulting groups also include perfluorinated groups. In the case of monosubstitution, fluorine or chlorine substitution may be at any desired position, but is preferably at the ω position.

In the context of the present invention, “alkylene” or “alkylene bridge” —unless otherwise defined in the description or in the claims—1, 2, 3, 4, 5, 6 in the chain. Represents a divalent aliphatic hydrocarbon group having 7 or 8 carbon atoms, mono- or polysubstituted with halogen, CN, carboxyl, nitro, alkanyl, alkoxy, —NH ₂ or —N (alkanyl) ₂ However, they may be poly-substituted by the same or different substituents. “Alkylene” or “alkylene bridge” preferably means a straight-chain saturated aliphatic group having 1, 2, 3, 4, 5, 6 carbon atoms, unsubstituted or substituted by fluorine. Substituted or polysubstituted, especially meaning —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, — (CH ₂ ) ₄ —, —CF ₂ CF ₂ — or — (CF ₂ ) ₄ — To do.

In the context of the present invention, the term “aralkyl” refers to an arylalkyl group, ie a group in which an aryl substituent is connected to an atom, chain, other group or functional group via an alkyl bridge. The alkyl bridge is preferably a saturated divalent hydrocarbon group (“alkylene”), in particular methylene (—CH ₂ —) or ethylene (—CH ₂ —CH ₂ —). Preferred examples of aralkyl groups are benzyl and phenethyl. For the purposes of the present invention, an “aralkyl-O-radical” is an aralkyl group that is linked to an additional atom, chain, other group or functional group through an oxygen atom attached to the alkyl bridge. It is. Preferred examples of aralkyl-O-radicals are O-benzyl and O—CH ₂ —CH ₂ -phenyl.

  In the context of the present invention, “halogen” represents fluorine, chlorine, bromine or iodine.

  In the context of the present invention, “acetal” refers to one equivalent of an alcohol (eg, ethanol) on an aldehyde (also referred to as “hemiacetal”) or two equivalents of alcohol (or two alcohols). Is the product of a (formal) addition reaction onto the carbonyl function of the aldehyde. In the context of the present invention, a “hydrate” of an aldehyde refers to one equivalent of water on the carbonyl function of the aldehyde (also referred to as “hemi” or “semi-hydrate”) or 2 of water. Means the product of the (formal) addition reaction of the two equivalents onto the carbonyl function of the aldehyde. It has to be noted here that aldehydes may also exist in equilibrium with the corresponding acetals (and hemiacetals) or their hydrates (and hemihydrates).

In the context of the present invention, the boronic ester is a group of formula -B (O-alkyl) ₂ and the two alkyl groups may be replaced by an alkylene bridge or other divalent hydrocarbon group.

  When the group or substituent of the compound used in the present invention or the compound itself used in the present invention can exist as a group, substituent or compound which may be optically active or stereoisomeric, for example, since it has an asymmetric center, these It is included in the present invention. These compounds are in isomerically pure state, e.g. pure enantiomers, diastereomers, E or Z isomers, trans or cis isomers, or mixtures of isomers in any desired ratio, e.g. Needless to say, it can exist in racemic, E / Z isomer mixtures or cis / trans isomer mixtures.

  In order to protect any reactive functional groups or substituents present in the compounds used in the methods of the invention from the reactions of the invention and / or from previous or subsequent reactions and / or undesired reactions in a series of operations. , Protecting groups that can be cleaved off again when the reaction is complete can be used. Methods of using suitable protecting groups are known to those skilled in the art and are described, for example, in T.W. W. Green, P.M. G. M.M. Wuts: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons (1999).

  The following examples illustrate the present invention without limiting it.

Above and below, the percent data represents weight percent. All temperatures are given in degrees Celsius. Tg is the glass transition temperature, cl. p. Is the clearing point. Further, C is a crystalline state, N is a nematic phase, Sm is a smectic phase, and I is an isotropic phase. The data between these symbols represents the phase transition temperature. Δn represents optical anisotropy (589 nm, 20 ° C.), Δε represents dielectric anisotropy (1 kHz, 20 ° C.), and γ ₁ represents rotational viscosity (mPa · s) at 20 ° C.

  The Δn and Δε values of the compounds of the invention are determined from a liquid crystal mixture consisting of 10% of each compound of the invention and 90% of commercially available liquid crystal ZLI-4792 (Merck, Darmstadt). Obtained by extrapolation.

  The following abbreviations are used above and below.

RT Room temperature DMSO Dimethyl sulfoxide DCC Dicyclohexylcarbodiimide TEMPO 2,2,6,6-tetramethylpiperidine N-oxide DIBAL-H Diisobutylaluminum hydride

    <Example 1>

３０ｍｇ（０．０３５ｍｍｏｌ）の塩化トリシクロヘキシルホスフィン（１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾール−２−イリデンベンジリデンルテニウム（ＩＶ）を、メタセシス触媒（Ｇｒｕｂｂｓ２触媒）として、０．３５ｍｏｌ（８４．８ｇ）の固体状態のジオレフィン（１）に、４０℃において窒素雰囲気下で数回に分けて加え、最初は２０ｍｇ、２回目は１時間後に１０ｍｇである。２時間後、エチレンの発生が事実上完了する。トルエン／ヘプタン（１：４）によりシリカゲルを通して濾過後、反応混合物より６１．３ｇ（理論の８１．７％）の（２）を得て、ヒドロホルミル化に直接使用し、（３）を得る。

30 mg (0.035 mmol) of tricyclohexylphosphine chloride (1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidenebenzylidene ruthenium (IV) was added to the metathesis catalyst (Grubbs 2 Catalyst) to 0.35 mol (84.8 g) of the solid diolefin (1) in several portions at 40 ° C. under a nitrogen atmosphere, initially 20 mg, the second being 10 mg after 1 hour. After 2 hours, the evolution of ethylene is virtually complete, after filtration through silica gel with toluene / heptane (1: 4), 61.3 g (81.7% of theory) of (2) is obtained from the reaction mixture, Use directly in hydroformylation to obtain (3).

For this purpose, 0.25 mol (53.55 g) of (2) in 200 ml of toluene was used at 60 bar and 150 ° C. with 3 g of tris (triphenylphosphine) carbonylrhodium (I) hydride and the synthesis gas Hydroformylation takes place over the course of 24 hours until the uptake of (H ₂ / CO = 1: 1) is complete. The reaction product is liberated from the solvent by evaporation in vacuo and the residue is filtered through silica gel with toluene / ethyl acetate (9: 1). In order to concentrate the trans component of the configuration of substituents in the formyltetrahydropyran component, the residue from which the filtrate has been evaporated (37.2 g = 69.5% of theory) is isomerized with a base.

  For this purpose, 1.8 ml of 20% aqueous sodium hydroxide solution are added to 37.2 g of a mixture of 190 ml of methanol and 48 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 1 hour. The mixture is then neutralized using hydrochloric acid and the solution is evaporated to dryness. 1 l of methyl tert-butyl ether is added to the evaporation residue, and the mixture is washed twice with 300 ml of water each time. After drying, the organic extract is evaporated, yielding 33 g of an 88% aldehyde mixture, which contains a little 4-formyltetrahydropyran in addition to trans-5-formyltetrahydropyran (3).

  To synthesize (4a), 33 g (0.135 mol) of (3) was refluxed for 2 hours, 27.1 g (0.135 mol) of 2- (4-trans-propylcyclohexyl)-in 250 ml of toluene. Warm on a water separator with 1,3-propanediol with 500 mg of toluene-4-sulfonic acid monohydrate until dehydration is complete.

  After cooling, 10 g of potassium carbonate is added with stirring, the mixture is filtered and the filtrate is evaporated to dryness. The evaporation residue is first filtered through silica gel with heptane / toluene (1: 1) and pure toluene.

  Two product fractions are obtained. From one, 12.4 g of the desired linear all-trans isomer (4a) (21.4% of theory) is obtained by recrystallization and from the other it is derived from 4-formyltetrahydropyran. 5 g of the wrong isomer of the dioxane derivative is obtained.

  (4a): C106N206.91I, Δε = 21.7, Δn = 0.0871.

<Example 2>
In a manner similar to Example 1, (4b) is obtained.

（４ｂ）：Ｃ８７Ｉ、Δε＝２３．７、Δｎ＝０．０５５０。

(4b): C87I, Δε = 23.7, Δn = 0.0550.

<Example 3>
In a manner similar to Example 1, (4c) is obtained.

（４ｃ）：Ｃ８８Ｎ（８７．９）Ｉ、Δε＝３５．８、Δｎ＝０．０８８０。

(4c): C88N (87.9) I, Δε = 35.8, Δn = 0.0880.

    <Example 4>

２００ｍｌのテトラヒドロフラン中に溶解された０．２ｍｏｌ（４８．８ｇ）の（３）と、１００ｍｌのテトラヒドロ中の２モル濃度の塩化アリルマグネシウム溶液とを、滴下により３０分かけて１５および２５℃の間で加える。添加が完了すれば、混合物を室温で更に２時間攪拌し、そして２００ｍｌの０．５Ｎ塩酸に投入し、有機相を分離し、水相をメチルｔｅｒｔ−ブチルエーテルで２回抽出する。混合された有機抽出物を水で洗浄し、乾燥し蒸発させる。蒸発残渣をトルエン／酢酸エチル（９８：２から９：１）でシリカゲルを通して濾過する。濾液より、３８．７ｇ（理論の６７．６％）のホモアリルアルコール（５）の異性体混合物を得る。

0.2 mol (48.8 g) of (3) dissolved in 200 ml of tetrahydrofuran and a 2 molar solution of allylic magnesium chloride in 100 ml of tetrahydro were added dropwise between 15 and 25 ° C. over 30 minutes. Add in. When the addition is complete, the mixture is stirred at room temperature for a further 2 hours and poured into 200 ml of 0.5N hydrochloric acid, the organic phase is separated and the aqueous phase is extracted twice with methyl tert-butyl ether. The combined organic extracts are washed with water, dried and evaporated. The evaporation residue is filtered through silica gel with toluene / ethyl acetate (98: 2 to 9: 1). From the filtrate, 38.7 g (67.6% of theory) of the homoallylic alcohol (5) isomer mixture is obtained.

  0.135 mol (38.7 g) of (5) and 0.135 mol (16.1 g) of propargyl bromide were dissolved in 80 ml of tetrahydrofuran, sodium hydroxide pellets (0.27 mol; 10.8 g),. Add to a vigorously stirred emulsion containing 5 ml water, 40 ml tetrahydrofuran and 6.75 mmol (2.46 g) N-cetyl-N, N, N-trimethylammonium bromide and warm to 45 ° C. at this temperature. For 16 hours. The mixture is then added to 1.5 l of ice water, the organic phase is separated and the aqueous phase is extracted three times with MTB ether. After drying and evaporating in advance, the combined organic phase residue is filtered through silica gel with toluene / heptane 2: 8. The filtrate is evaporated to give 34.3 g (78.4% of theory) of (6), which is used directly as a crude mixture in enyne metathesis to give (7).

  For this, 115 mg (0.14 mmol) of bis (tricyclohexylphosphine) benzylideneruthenium (IV) chloride (Grubbs1 catalyst) are added to 0.028 mol (9.4 g) of (6) in 20 ml of dichloromethane and the mixture is added. After stirring for 4 hours at room temperature and adding 115 mg of the same amount of catalyst, the mixture is stirred for a further 16 hours at room temperature. Evaporate, filter through silica gel with toluene / heptane (3: 7), dry the filtrate and recrystallize the resulting residue (1.0 g) first from ethanol and from heptane, identified as structure (7). 0.6 g of isomer is obtained.

  (7): C97I, Δε = 14.2, Δn = 0.0800.

  0.2 g of (7) for 6 hours at 10 bar hydrogen pressure at 90 ° C. in 5 ml of methanol and 1 ml of toluene using 0.1 g of tris (triphenylphosphine) rhodium chloride (I) Hydrogenate. After cooling, the reaction mixture is evaporated in vacuo and filtered through silica gel with toluene / heptane (3: 7). After drying, 0.15 g of (8) is obtained as an oil.

    <Example 5>

化合物（９）を、対応するホモアリルアルコール前駆体から２−（ブロモメチル）アクリレートを使用して、Ｏ−アルキル化により調製する。このために、８０ｍｌのテトラヒドロフラン中の０．２ｍｏｌ（７６．１ｇ）のホモアリルアルコールを、温度を２０℃に保ちながら窒素の保護ガス雰囲気下で８０ｍｌのテトラヒドロフラン中の６０％の懸濁液としての０．２ｍｏｌ（８．０ｇ）の水素化ナトリウムに、滴下により攪拌および氷水を使用して外部より冷却しながら加える。約２時間後、水素の発生が完了する。そして、４０ｍｌのテトラヒドロフラン中の０．２ｍｏｌ（３８．６ｇ）の酢酸ブロモメチルを、温度が２５℃を超えない速度で滴下により加える。引き続き、攪拌を室温で更に１６時間継続する。そして、反応混合物を６００ｍｌの氷水に投入し、１ＮのＨＣｌを使用して中和し、有機相を分離する。水相をメチルｔｅｒｔ−ブチルエーテルで２回抽出後に、混合された有機相を蒸発させて乾燥し、トルエン／メチルｔｅｒｔ−ブチルエーテル（３：１）でシリカゲルを通して濾過する。濾液を蒸発させた残渣は、６５．９ｇ（理論の７１％）のアルキル化生成物（９）を含む。

Compound (9) is prepared by O-alkylation using 2- (bromomethyl) acrylate from the corresponding homoallylic alcohol precursor. For this purpose, 0.2 mol (76.1 g) of homoallyl alcohol in 80 ml of tetrahydrofuran as a 60% suspension in 80 ml of tetrahydrofuran under a protective atmosphere of nitrogen while keeping the temperature at 20 ° C. To 0.2 mol (8.0 g) of sodium hydride, it is added dropwise with stirring and cooling from outside using ice water. After about 2 hours, hydrogen evolution is complete. Then 0.2 mol (38.6 g) of bromomethyl acetate in 40 ml of tetrahydrofuran is added dropwise at a rate such that the temperature does not exceed 25 ° C. Subsequently, stirring is continued for an additional 16 hours at room temperature. The reaction mixture is then poured into 600 ml of ice water, neutralized using 1N HCl and the organic phase separated. After extracting the aqueous phase twice with methyl tert-butyl ether, the combined organic phases are evaporated to dryness and filtered through silica gel with toluene / methyl tert-butyl ether (3: 1). The residue from evaporation of the filtrate contains 65.9 g (71% of theory) of the alkylated product (9).

  0.1 mol (49.2 g) of (9) is warmed to 60 ° C. with 25 ml of toluene, and 212 mg of Grubbs 2 catalyst each is divided into 4 portions (1 mol% total) and added every hour. When the evolution of ethylene is complete, the mixture is filtered through silica gel with toluene / methyl tert-butyl ether. The filtrate is evaporated leaving 28.8 g (62% of theory) of the dihydropyran ester (10).

  0.05 mol (23.2 g) of dihydropyran ester (10) was dissolved in 2 g of tris (triphenylphosphine) rhodium chloride (I) in 10 ml of hydrogen pressure at 12 hours and 300 ml of methanol and 60 ml of toluene at 100 ° C. ) To hydrogenate. The solvent is evaporated and the residue is filtered through silica gel with toluene / methyl tert-butyl ether to give the hydrogenated ester (11) (18.4 g = 79% of theory).

  For the synthesis of aldehyde (12), 0.039 mol (18.4 g) of ester (11) in 80 ml of toluene was cooled to −70 ° C. and 32.5 ml of hydrogenated 1,2-N in toluene. -Add diisobutylaluminum (DIBAL-H) at -70 ° C with stirring, complete the addition after 4 hours, and continue stirring, then add the mixture to 100 ml of cold 1N HCl while it is still cold. The organic phase is washed with aqueous sodium hydrogen carbonate solution and water, dried and evaporated. The evaporation residue of aldehyde (12) can be used directly in the synthesis of (4c) as described in Example 1.

<Example 6>
The synthesis of (13) is also performed in the same manner as in Example 5.

＜例７＞
（１４）の合成も例５に類似して行うが、この場合、アルデヒド（３）とである。

<Example 7>
The synthesis of (14) is also analogous to Example 5, but in this case with aldehyde (3).

（１４）：Ｃ９１ＳｍＨ（６３）Ｎ２０３．４Ｉ、Δε＝２１．３、Δｎ＝０．０８８０。

(14): C91SmH (63) N203.4I, Δε = 21.3, Δn = 0.0880.

    <Example 8>

ブロモ酢酸のＮａ塩を使用してメタリルアルコールをアルキル化して調製される（テトラヒドロフラン中１６時間６０℃）酸（１５）を、脱水剤としてジシクロヘキシルカルボジイミド（ＤＣＣＩ）およびジクロロメタン中の４−ジメチルアミノピリジン存在下、アリルアルコールと反応させ（１６時間、室温）、エステル（１６）を得る。これを、クロロトリメチルシラン存在下でリチウムジイソプロピルアミドによりクライゼン−アイルランド法で再配置し（１７）を得る（加えて−７５℃、そして室温で１６時間、溶媒はテトラヒドロフラン）。（１７）を、３，４，５−トリフルオロフェノールを使用し、ＤＣＣＩおよびＤＡＰ存在下でエステル化し、（１８）を得る。ジヒドロフランエステル（１９）を得る閉環を、固体状態でＮ_２保護ガス下８０℃まで温め、０．５ｍｏｌ％のＧｒｕｂｂｓ２触媒を加え、その間、エチレンの発生による１５分間の発泡後、混合物を８０℃で更に５分放置して行う。トルエンでシリカゲルを通す濾過後、単離（理論の６５％）されたジヒドロピランエステル（１９）（１１ｇ）を、１７時間、１００℃、１１ｂａｒ、Ｗｉｌｋｉｎｓｏｎ触媒（２ｍｏｌ％）、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用し、６０ｍｌのエチルメチルケトンおよび６０ｍｌのトルエン中で水素化し、テトラヒドロピランエステル（２０）を得る。

Prepared by alkylation of methallyl alcohol using Na salt of bromoacetic acid (16 hours at 60 ° C. in tetrahydrofuran) acid (15) is used as a dehydrating agent dicyclohexylcarbodiimide (DCCI) and 4-dimethylaminopyridine in dichloromethane React with allyl alcohol in the presence (16 hours, room temperature) to give ester (16). This is rearranged by the Claisen-Ireland method with lithium diisopropylamide in the presence of chlorotrimethylsilane to give (17) (plus -75 ° C. and 16 hours at room temperature, solvent is tetrahydrofuran). (17) is esterified using 3,4,5-trifluorophenol in the presence of DCCI and DAP to give (18). The ring closure to obtain the dihydrofuran ester (19) was warmed to 80 ° C. under N ₂ protective gas in the solid state and 0.5 mol% of Grubbs 2 catalyst was added during which, after 15 minutes of foaming by ethylene evolution, the mixture was heated to 80 ° C. Leave for another 5 minutes. After filtration through silica gel with toluene, the isolated (65% of theory) dihydropyran ester (19) (11 g) was converted to 100 ° C., 11 bar, Wilkinson catalyst (2 mol%), Tris chloride (triphenylphosphine) for 17 hours. ) Hydrogenation in 60 ml of ethyl methyl ketone and 60 ml of toluene using rhodium (I) gives the tetrahydropyran ester (20).

  Using DIBAL-H, 0.05 mol (13.7 g) of (20) was reduced as described in Example 3 for reducing ester (11) to aldehyde (12) to give aldehyde (21) Get.

<Example 9>
Analogously to Example 8, aldehyde (23) is prepared from ester (22).

＜例１０＞

<Example 10>

ホモアリルアルコールのアリル化および（２６）の閉環メタセシスによるジヒドロピラニルエステル（２７）の合成を、例３からジヒドロピラニルエステル（１０）のそれに類似して行う。５１ｇのエステル（２７）を、９時間の行程に渡り１０ｂａｒの水素圧、２３℃で、６００ｍｌのｎ−ヘプタン中、１２ｇのＰｄ／Ｃ（５％）を使用して水素化し、テトラヒドロピランエステル（２８）の異性体混合物を得る。

The synthesis of dihydropyranyl ester (27) by allylation of homoallylic alcohol and ring closure metathesis of (26) is carried out analogously to that of dihydropyranyl ester (10) from Example 3. 51 g of ester (27) was hydrogenated using 12 g of Pd / C (5%) in 600 ml of n-heptane over 10 hours at 10 bar hydrogen pressure and 23 ° C. to give the tetrahydropyran ester ( 28) is obtained as an isomer mixture.

  0.074 mol (21 g) of the isomeric ester (28) is refluxed with nitrogen in 0.08 mol (4.55 g) of KOH for 6 hours in 200 ml of methanol under nitrogen and stirred for a further 12 hours at room temperature. The solvent is then substantially removed and the residue is treated with 90 ml of 1N HCl, filtered off and washed with water. Toluene is added to the residue and evaporated again for azeotropic drying. During alkali saponification, most of the cis ester or cis acid is isomerized to the trans derivative, leaving 17 g (90% of theory) of tetrahydropyranic acid (29).

0.067 mol (17 g) of acid (29) in 90 ml of tetrahydrofuran is added dropwise to a mixture of 0.05 mol (1.91 g) of LiAlH ₄ in 10 ml of tetrahydrofuran at such a rate that only a gentle reflux occurs. When the addition is complete, the mixture is warmed to reflux for an additional 6 hours. The mixture is allowed to cool and 75 ml of chilled 2N HCl is added with stirring. After separation of the two phases, the aqueous phase is further extracted with 100 ml of methyl tert-butyl in each case. The mixed organic phase is washed with 50 ml of saturated NaHCO ₃ solution and water until neutralized, dried and evaporated to give 12.3 g (76.4% of theory) of alcohol (30).

  The alcohol (30) is oxidized to the aldehyde (31) by the Swern method. For this purpose, 0.0525 mol (12.5 g) of trifluoroacetic anhydride in 15 ml of dichloromethane was added to 0.0635 mol (4.95 g) of dimethyl sulfoxide in 60 ml of dichloromethane at a temperature of −60 Add with stirring at -60 ° C while maintaining at 0 ° C. After the addition was complete and stirring at −60 ° C. for a further 10 minutes, 0.05 mol (12.0 g) of alcohol (30) in 40 ml of dichloromethane was added dropwise with stirring, followed by dropwise addition for 5 minutes and then The temperature is held at −60 ° C. for 10 minutes. The mixture is then warmed to room temperature and 18.5 ml of triethylamine is added dropwise over 10 minutes at a rate such that the temperature does not exceed 30 ° C. with occasional cooling from the outside. When the addition is complete, the mixture is allowed to cool to room temperature for 30 minutes and the reaction mixture is washed with 100 ml of water. The aqueous phase is extracted with 50 ml of dichloromethane. After drying and evaporation, 6.4 g (54% of theory) of aldehyde (31) is obtained from the combined organic phases.

    <Example 11>

メタセシスにより形成されたジヒドロピラン（３２）を、例１に類似のヒドロホルミル化によりアルデヒド（３３）に転化し、エン−カルボニル反応中でホモアリルアルコール（３４）と反応させ、最初にブロモテトラヒドロピラン（３５）を得る。

Dihydropyran (32) formed by metathesis was converted to aldehyde (33) by hydroformylation similar to Example 1 and reacted with homoallyl alcohol (34) in an ene-carbonyl reaction, first bromotetrahydropyran ( 35).

The synthesis of homo-allylic alcohol, carried out via the acetate of zinc alcohol (38) which can be prepared by classical methods by reaction with gaseous formaldehyde in the ₂ presence of zinc powder and CoBr.

このために、１ｍｌのトリフルオロ酢酸を使用して亜鉛を活性化したあと、分離可能なフラスコ中で１．０ｍｏｌ（３０ｇ）のパラホルムアルデヒドを２２０℃まで加熱して形成されるガス状ホルムアルデヒドを、４００ｍｌのアセトニトリル中の２６ｇの亜鉛粉（０．４ｍｏｌ）、１３．２ｇ（０．０６ｍｏｌ）のＣｏＢｒ_２および０．２ｍｏｌ（５１．２ｇ）の（３８）の溶液中を通過させる。導入が終了すれば、混合物を室温で更に１２時間攪拌する。そして、混合物を１００ｍｌの２ＮＨＣｌに投入し、有機相を分離して取り除き、水相をメチルｔｅｒｔ−ブチルで２回抽出する。混合された有機相を蒸発させ、残る残渣をトルエン／酢酸エチル（７：３）でシリカゲルを通して濾過し、より極性の画分を蒸発させ、ホモアリルアルコール（３４）を粗材料として理論の４８％の収率（２１．９ｇ）で得る。

For this purpose, gaseous formaldehyde formed by activating zinc using 1 ml of trifluoroacetic acid and then heating 1.0 mol (30 g) of paraformaldehyde to 220 ° C. in a separable flask, Pass through a solution of 26 g zinc powder (0.4 mol), 13.2 g (0.06 mol) CoBr ₂ and 0.2 mol (51.2 g) (38) in 400 ml acetonitrile. When the introduction is complete, the mixture is stirred for another 12 hours at room temperature. The mixture is then poured into 100 ml of 2N HCl, the organic phase is separated off and the aqueous phase is extracted twice with methyl tert-butyl. The combined organic phases are evaporated, the remaining residue is filtered through silica gel with toluene / ethyl acetate (7: 3), the more polar fraction is evaporated and homoallylic alcohol (34) is used as crude material, 48% of theory. In a yield of 21.9 g.

Initially 0.09 mol (20.5 g) of homoallylic alcohol (34) is introduced at 0 ° C. with 0.69 mol (14.0 g) of aldehyde (33) and 5 mol% BiBr ₃ (2 g). And until HBr is generated from the washing bottle in front of the reaction vessel (about 10 minutes) as much as is generated from the bubble counter behind the reaction vessel, the temperature of HBr as a gas is between 5 and 20 ° C. Pass through while cooling from outside. The mixture is then poured quickly into ice-cold saturated sodium bicarbonate solution, the organic phase is washed with water, dried and evaporated. The isomeric mixture of isomers bromotetrahydropyran (35) is used in the next reaction step in the formation of crude purification to eliminate HBr to give dihydro (36).

0.057 mol of the isomer mixture (36) from the previous step (23.3 g, 63.3% of theory) was refluxed for 6 hours with 0.086 mol (10.2 ml) of 1,1 in 40 ml of toluene. Warm with 5-diazabicyclo [4.3.0] on-ene. After cooling, the pH is adjusted to 3 using water and dilute sulfuric acid and then the mixture is mixed vigorously. After separation, the organic phase is washed with saturated NaHCO ₃ solution and water and filtered through silica gel. Evaporation yields an isomer mixture of 15.7 g (84% of theory) of dihydropyran (36).

  The hydrogenation of isomer mixture (36) (15.7 g) was dissolved in 300 ml methanol and 75 ml toluene and 0.48 mmol (448 mg) tris (triphenylphosphine) rhodium chloride at 10 bar, 90 ° C. for 20 hours. Hydrogenation is carried out using (I) as a catalyst. After evaporation of the solvent, the residue is filtered through silica gel with toluene. Repeat fractional crystallization from ethanol and heptane to obtain 0.5 g of (37).

    <Example 12>

窒素下、ジエチルエーテル中の臭化アリルマグネシウムの１Ｍ溶液の８００ｍｌを、５００ｍｌのＴＨＦ中の２７２ｇ（８００ｍｍｏｌ）のアルデヒドの溶液に、２５℃より低い温度で加える。反応物を室温で一晩攪拌し、氷水に加え、引き続いてメチルｔｅｒｔ−ブチルエーテルで抽出する。有機相を飽和ＮａＣｌ溶液で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。得られる残渣をシリカゲルに通す。

Under nitrogen, 800 ml of a 1M solution of allylmagnesium bromide in diethyl ether is added to a solution of 272 g (800 mmol) of aldehyde in 500 ml of THF at a temperature below 25 ° C. The reaction is stirred at room temperature overnight and added to ice water followed by extraction with methyl tert-butyl ether. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting residue is passed through silica gel.

１０３ｇ（８１％、２２０ｍｍｏｌ）のアルコールおよび２１ｇ（８０ｍｍｏｌ）のトリフェニルホスフィンを５００ｍｌの酢酸エチルに溶解し、５００ｍｇの酢酸ロジウム２量体を加える。ヒドロホルミル化を２５ｂａｒの合成ガスおよび１００℃で行う。反応溶液を蒸発させ、シリカゲルを通す。

103 g (81%, 220 mmol) alcohol and 21 g (80 mmol) triphenylphosphine are dissolved in 500 ml ethyl acetate and 500 mg rhodium acetate dimer is added. The hydroformylation is carried out at 25 bar synthesis gas and 100 ° C. The reaction solution is evaporated and passed through silica gel.

窒素下、２４．５ｍｌ（３２０ｍｍｏｌ）の塩化メタンスルホニルを、５００ｍｌのジクロロメタン中の１００ｇ（２４０ｍｍｏｌ）のラクトンおよび１０１ｍｌ（２９９ｍｍｏｌ）のトリエチルアミンの溶液に、０〜５℃で加える。反応物を一晩、室温で攪拌する。反応物を水に加え、メチルｔｅｒｔ−ブチルエーテルで抽出する。有機相を飽和ＮａＣｌ溶液で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。得られる残渣をシリカゲルに通す。

Under nitrogen, 24.5 ml (320 mmol) of methanesulfonyl chloride is added at 0-5 ° C. to a solution of 100 g (240 mmol) of lactone and 101 ml (299 mmol) of triethylamine in 500 ml of dichloromethane. The reaction is stirred overnight at room temperature. The reaction is added to water and extracted with methyl tert-butyl ether. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting residue is passed through silica gel.

６０ｇ（１４８ｍｍｏｌ）のエノールエーテルを３００ｍｌのトルエンに溶解し、９．８ｇ（１５ｍｍｏｌ）のトリス（２，４−ジ−ｔｅｒｔ−ブチルフェニル）ホスフィンおよび３９０ｍｇ（１．５ｍｍｏｌ）のジカルボニルアセチルアセトナートロジウム（Ｉ）を加える。ヒドロホルミル化を１００ｂａｒの合成ガスおよび１００℃で行う。溶液を引き続き蒸発させ、残渣をシリカゲルに通して、アルデヒドのシス／トランス混合物を得る。

60 g (148 mmol) of enol ether is dissolved in 300 ml of toluene, 9.8 g (15 mmol) of tris (2,4-di-tert-butylphenyl) phosphine and 390 mg (1.5 mmol) of dicarbonylacetylacetonatodium. Add (I). The hydroformylation is carried out at 100 bar synthesis gas and 100 ° C. The solution is subsequently evaporated and the residue is passed through silica gel to give a cis / trans mixture of aldehydes.

  The aldehyde proton signals are δ = 9.69 ppm and δ = 9.88 ppm.

アルデヒド（４３）を引き続き２−エチル−１，３−プロパンジオールと反応させて、ジオキサン（４ｃ）を得る（例３参照）。このために、４４．５ｇ（１１０ｍｍｏｌ）のアルデヒド（４３）および１２．０ｇ（１１５ｍｍｏｌ）のジオール２、エチル−１，３−プロパンジオールを２５０ｍｌのトルエンに溶解し、４００ｍｇのｐ−トルエンスルホン酸一水和物を加え、アルデヒドの転化が完了するまで（ＴＬＣ）、混合物を水分離器上で還流下により加熱する。冷却された反応物を飽和炭酸水素ナトリウム溶液で３回洗浄し、乾燥し、シリカゲル（トルエン／ヘプタン７：３；トルエン；トルエン／酢酸エチル９５：５）を通す。生成物を含む画分を蒸発させ、残渣をエタノールより−２０℃で再結晶する。

Aldehyde (43) is subsequently reacted with 2-ethyl-1,3-propanediol to give dioxane (4c) (see Example 3). For this purpose, 44.5 g (110 mmol) of aldehyde (43) and 12.0 g (115 mmol) of diol 2, ethyl-1,3-propanediol are dissolved in 250 ml of toluene and 400 mg of p-toluenesulfonic acid Hydrate is added and the mixture is heated under reflux on a water separator until aldehyde conversion is complete (TLC). The cooled reaction is washed 3 times with saturated sodium bicarbonate solution, dried and passed through silica gel (toluene / heptane 7: 3; toluene; toluene / ethyl acetate 95: 5). The fractions containing the product are evaporated and the residue is recrystallized from ethanol at -20 ° C.

  (4c): C88N (87.9) I; Δε = 35.8; Δn = 0.0880.

    <Example 13>

１００ｍｌのトルエン中の９．０ｇ（０．０３８ｍｍｏｌ）の３−（４’−ペンチルシクロヘキシル）−２Ｈ−３，４−ジヒドロピラン（４４）を０．４ｇのジコバルトオクタカルボニルと２時間、１４０℃、３００ｂａｒで、１．７ｌの合成ガス（Ｈ_２／ＣＯ＝１：１）下で反応させる。冷却後、反応溶液を蒸発させ、残渣をヘプタン／トルエン（１：１）でシリカゲルを通して濾過する。蒸発後、濾液より９．１ｇの薄茶色の油状の残渣を得て、アルコール（４６）のアルデヒド（４５）に対する比は４：１である。混合物をアルデヒド（４５）の酸化に直接利用する（例１０のＳｗｅｒｎ酸化工程も参照）。

9.0 g (0.038 mmol) of 3- (4′-pentylcyclohexyl) -2H-3,4-dihydropyran (44) in 100 ml of toluene with 0.4 g of dicobalt octacarbonyl for 2 hours at 140 ° C. The reaction is carried out at 300 bar under 1.7 l of synthesis gas (H ₂ / CO = 1: 1). After cooling, the reaction solution is evaporated and the residue is filtered through silica gel with heptane / toluene (1: 1). After evaporation, 9.1 g of a light brown oily residue is obtained from the filtrate, the ratio of alcohol (46) to aldehyde (45) being 4: 1. The mixture is used directly for the oxidation of aldehyde (45) (see also the Swern oxidation step of Example 10).

Claims (13)

Formyltetrahydropyran derivatives selected from formulas IIa, IIb and IIc:

(However,
R ¹¹ and R ¹² are F, CF ₃ , OCF ₃ , CN, NCS, SF ₅ or an alkyl group having 1 to 15 C atoms, the group being mono- or polysubstituted by halogen, provided that In addition, one or more CH ₂ groups in these groups may be —C≡C—, —CH═CH—, —O—, —S—, so that heteroatoms in the chain are not directly bonded to each other. _{-SO -, - SO 2 -,} - (CO) O- or -O (CO) - may be replaced by,
R ¹³ is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted or It is either monosubstituted by CN, which is monosubstituted or polysubstituted by halogen, provided that in addition, one or more CH ₂ groups in these groups, as hetero atoms in the chain are not bonded directly to one another , —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, — (CO) O— or —O (CO) — may be substituted. ,
L ¹ and L ² are each independently equal to H, Cl or F;
A ¹ and A ² , independently of one another, may be the same or different, rotated or mirror image,

Represents
Y ¹ , Y ² and Y ³ are independently of each other hydrogen, halogen, CN, NCS, SF ₅ , C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, OC _1-6. -Alkanyl, OC _2-6 -alkenyl or OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ¹ and Z ² are single bond, only alkylene bridge which is monosubstituted or polysubstituted by unsubstituted or F and / or Cl have from 1 to 6 carbon atoms, or _{-CH 2 O -, - OCH 2} -, - (CO) _{O -, - O (CO)} -, - CF 2 O -, - OCF 2 -, - CH 2 CH 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
a is 0 or 1,
b is 0 or 1,
However, the compound of the following formula is not included. )

The formyltetrahydropyran derivatives according to claim 1, wherein R ¹¹ to ¹³ represent F, OCF ₃ , CF ₃ , OCF ₂ H, SF ₅ . Formyltetrahydropyran derivatives selected from formulas IIa, IIb and IIc:

(However,
R ¹¹ and R ¹² are F, CF ₃ , OCF ₃ , CN, NCS, SF ₅ or an alkyl group having 1 to 15 C atoms, the group being mono- or polysubstituted by halogen, provided that In addition, one or more CH ₂ groups in these groups may be —C≡C—, —CH═CH—, —O—, —S—, so that heteroatoms in the chain are not directly bonded to each other. _{-SO -, - SO 2 -,} - (CO) O- or -O (CO) - may be replaced by,
R ¹³ is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted or It is either monosubstituted by CN, which is monosubstituted or polysubstituted by halogen, provided that in addition, one or more CH ₂ groups in these groups, as hetero atoms in the chain are not bonded directly to one another , —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, — (CO) O— or —O (CO) — may be substituted. ,
L ¹ and L ² are each independently equal to H, Cl or F;
A ¹ and A ² , independently of one another, may be the same or different, rotated or mirror image,

Represents
Y ¹ , Y ² and Y ³ are independently of each other hydrogen, halogen, CN, NCS, SF ₅ , C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, OC _1-6. -Alkanyl, OC _2-6 -alkenyl or OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ¹ and Z ² are single bond, only alkylene bridge which is monosubstituted or polysubstituted by unsubstituted or F and / or Cl have from 1 to 6 carbon atoms, or _{-CH 2 O -, - OCH 2} -, - (CO) _{O -, - O (CO)} -, - CF 2 O -, - OCF 2 -, - CH 2 CH 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
a is 0 or 1,
b is 0 or 1,
However, the compound of the following formula is not included. )

A preparation method of
A process for the preparation comprising hydroformylating a compound of formula IIIa, IIIb and / or IIIc.

(Where
R ¹ has the meaning of R ¹¹ in formulas IIIa and IIIb, the meaning of R ¹³ in formula IIIc,
A ¹ and A ² are as described above,
Z ¹ and Z ² are as described above,
a is 0 or 1,
b is 0 or 1,
c is 0. ) 4. The compounds of formula IIIb and / or IIIc are respectively prepared from the following compounds of formula X and / or XIII by leaving the hydroxyl group directly or after conversion to a leaving group: The method described.

(However, A ¹ , A ² , A ³ , Z ¹ , Z ² , Z ³ , a, b, c and R ¹ are independently as defined in claim 3.) 5. A process according to claim 4, wherein the compounds of formula X and XIII are prepared from compounds of formula VI and XII, respectively, by a hydroformylation step and ring closure.

(However, A ¹ , A ² , A ³ , Z ¹ , Z ² , Z ³ , a, b, c and R ¹ are independently as defined in claim 4.)   Hydroformylation of compounds of formula IIIa, IIIb or IIIc can be catalyzed by using both carbon monoxide and hydrogen simultaneously or by subsequent hydrolysis of intermediates using hydrosilanes or formates instead of hydrogen. Or catalytically using transition metals, wherein the catalyst is a rhodium (Rh), ruthenium (Ru) or cobalt (Co) based catalyst. The method of any one of -5.   The catalytic reaction is performed using transition metal complexes of rhodium or cobalt metal composed of cobalt compounds with carbonyl ligands or rhodium compounds with phosphorus-containing ligands. The method of claim 6. Formyltetrahydropyran derivatives selected from formulas IIa, IIb and IIc:

(However,
R ¹¹ and R ¹² are F, CF ₃ , OCF ₃ , CN, NCS, SF ₅ or an alkyl group having 1 to 15 C atoms, the group being mono- or polysubstituted by halogen, provided that In addition, one or more CH ₂ groups in these groups may be —C≡C—, —CH═CH—, —O—, —S—, so that heteroatoms in the chain are not directly bonded to each other. _{-SO -, - SO 2 -,} - (CO) O- or -O (CO) - may be replaced by,
R ¹³ is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted or It is either monosubstituted by CN, which is monosubstituted or polysubstituted by halogen, provided that in addition, one or more CH ₂ groups in these groups, as hetero atoms in the chain are not bonded directly to one another , —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, — (CO) O— or —O (CO) — may be substituted. ,
L ¹ and L ² are each independently equal to H, Cl or F;
A ¹ and A ² , independently of one another, may be the same or different, rotated or mirror image,

Represents
Y ¹ , Y ² and Y ³ are independently of each other hydrogen, halogen, CN, NCS, SF ₅ , C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, OC _1-6. -Alkanyl, OC _2-6 -alkenyl or OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ¹ and Z ² are single bond, only alkylene bridge which is monosubstituted or polysubstituted by unsubstituted or F and / or Cl have from 1 to 6 carbon atoms, or _{-CH 2 O -, - OCH 2} -, - (CO) _{O -, - O (CO)} -, - CF 2 O -, - OCF 2 -, - CH 2 CH 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
a is 0 or 1,
b is 0 or 1,
However, the compound of the following formula is not included. )

A preparation method of
A process for the preparation comprising reacting a compound of formula IV by one or more reactions of IV comprising at least one reduction step.

(Where
R ¹ has the meaning of R ¹¹ or R ¹³ ;
R ³ represents CN, COOH, CONHR ⁴ , COOR ⁴ ;
R ⁴ represents alkyl, aralkyl or (optionally substituted) aryl;
A ¹ and A ² are as described above,

Z ¹ and Z ² are as described above,
a is 0 or 1,
b is 0 or 1,
c is 0. )   The corresponding 2,5-disubstituted 3,6-dihydro-2H-pyran or 3 prepared from the appropriately substituted dienes by catalytic ring-closing metathesis that eliminates ethylene in the presence of a Grubbs catalyst. 9. The method of claim 8, wherein the tetrahydropyran compounds of formula IV are prepared by hydrogenating 1,6-disubstituted 3,4-dihydro-2H-pyran.   10. The reduction of compounds of formula IV to aldehydes of formula II is carried out with reduced metals, metal hydrides, alkyl metal compounds or low-valent boron compounds. The method described.   11. The reduction of a compound of formula IV is carried out using diisobutylaluminum hydride, dialkylaluminum hydrides or amino hydrides or alkoxy-substituted lithium aluminums according to any one of claims 8-10. The method described. Formyltetrahydropyran derivatives selected from formulas IIa, IIb and IIc:

(However,
R ¹¹ and R ¹² are F, CF ₃ , OCF ₃ , CN, NCS, SF ₅ or an alkyl group having 1 to 15 C atoms, the group being mono- or polysubstituted by halogen, provided that In addition, one or more CH ₂ groups in these groups may be —C≡C—, —CH═CH—, —O—, —S—, so that heteroatoms in the chain are not directly bonded to each other. _{-SO -, - SO 2 -,} - (CO) O- or -O (CO) - may be replaced by,
R ¹³ is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , boronic acid ester, an alkyl group having 1 to 15 C atoms, which group is unsubstituted or It is either monosubstituted by CN, which is monosubstituted or polysubstituted by halogen, provided that in addition, one or more CH ₂ groups in these groups, as hetero atoms in the chain are not bonded directly to one another , —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, — (CO) O— or —O (CO) — may be substituted. ,
L ¹ and L ² are each independently equal to H, Cl or F;
A ¹ and A ² , independently of one another, may be the same or different, rotated or mirror image,

Represents
Y ¹ , Y ² and Y ³ are independently of each other hydrogen, halogen, CN, NCS, SF ₅ , C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, OC _1-6. -Alkanyl, OC _2-6 -alkenyl or OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ¹ and Z ² are single bond, only alkylene bridge which is monosubstituted or polysubstituted by unsubstituted or F and / or Cl have from 1 to 6 carbon atoms, or _{-CH 2 O -, - OCH 2} -, - (CO) _{O -, - O (CO)} -, - CF 2 O -, - OCF 2 -, - CH 2 CH 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
a is 0 or 1,
b is 0 or 1,
However, the compound of the following formula is not included. )

A preparation method of
A preparation process characterized in that the alcohol of formula V is oxidized.

(Where
R ¹ has the meaning of R ¹¹ or R ¹³ ;
A ¹ and A ² are as described above,

Z ¹ and Z ² are as described above,
a is 0 or 1,
b is 0 or 1,
c is 0. ) Oxidation of compounds of formula V can be carried out using CrO ₃ , iodine reagents, DMSO / DCC, DMSO / oxalyl dichloride, acetone / Al (O-alkyl) ₃ or N-oxidized 2,2,6,6-tetramethylpiperidine. The process according to claim 12, characterized in that it is carried out by an oxidation process using NaOCl catalyzed with transition metal catalysts and avoiding excessive oxidation to carboxylic acids or carboxylic esters. Method.