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    • 专利摘要:
    One or more halogen atoms, trifluoromethoxy groups, dialkylaminos are characterized by deprotonation of aromatic compounds using alkyl- or arylmetal compounds or metal hydrides in the presence of catalytic amounts of secondary metal amides. A method for preparing ortho-substituted arylmetal compounds by reacting deprotonated aromatic compounds having hydrogen atoms at the ortho position relative to the group, nitrile group, alkoxy group or dialkylamido group and reacting the compound with an electrophilic reagent It is about.
    公开号:KR20000062207A
    申请号:KR1019990058665
    申请日:1999-12-17
    公开日:2000-10-25
    发明作者:스티아스니한스-크리스티안；라이펜래트볼커
    申请人:플레믹 크리스티안；메르크 파텐트 게엠베하；
    IPC主号:
    专利说明:

    PROCESS FOR THE PREPARATION OF ORTHO-SUBSTITUTED ARYLMETAL COMPOUNDS AND THEIR REACTION WITH ELECTROPHILIC REAGENTS}
    One or more halogen atoms, trifluoromethoxy groups, dialkylaminos are characterized by deprotonation of aromatic compounds using alkyl- or arylmetal compounds or metal hydrides in the presence of catalytic amounts of secondary metal amides. By deprotonating an aromatic compound having a hydrogen atom at the ortho position to a group, a nitrilo group, an alkoxy group or a dialkylamido group to prepare an ortho-substituted arylmetal compound and reacting the compound with an electrophilic reagent It is about a method.
    Substituted aromatic compounds are useful intermediates for the synthesis of high value-added end products or by themselves in the electronics industry, such as liquid crystals, in crop protection, such as pesticides, or in the preparation of pharmaceutically very active substances, such as dopamine receptor blockers, anti-emetic or antipsychotics. Final product.
    In particular, the above applies to aromatic compounds substituted at the ortho position with respect to halogen atoms, trifluoromethoxy groups, dialkylamino groups, nitrile groups, alkoxy groups or dialkylamido groups.
    Various methods for preparing such compounds are given in the literature.
    Thus, for example, D. L. Ladd et al. Org. Chem. 46, 203 (1981), metallization of 1,4-difluorobenzene with butyllithium at a temperature below -65 ° C results in the formation of 1-lithium-2,5-difluorobenzene. And reacting it with trimethyl borate at the same (low) temperature to give dimethyl 2,5-difluorobenzeneboronate (Scheme 1).
    Boronates are oxidized with hydrogen peroxide to produce the corresponding phenols.
    This reaction sequence is also described in WO 89/2425, which relates to the preparation of 2,3-difluorophenol, wherein the reaction temperature does not change and the reaction conditions only slightly change (Scheme 2).
    Further, WO 89/2425 discloses a process for preparing liquid crystal 2,3- or 2 ', 3'-difluoro-p-tert-phenylene starting from 1,2-difluorobenzene. It describes. International Patent Publication No. 89/8629 describes a method for synthesizing another liquid crystal compound having a 2,3-difluoro-1,4-phenylene group. In the above process, 1,2-difluorobenzene or 1-substituted 2,3-difluorobenzene are deprotonated using a strong base, usually n-butyllithium, and the resulting 2,3 The difluorophenyllithium compound reacts with the electrophilic reagent.
    The reason for using a low reaction temperature is that the stability of the ortho-haloaryl metal compound is insufficient. For example, a 2,3-difluorophenyllithium derivative forms a 1-fluoro-2,3-benzene derivative and removes lithium fluoride above -50 ° C, wherein the 1-fluoro-2,3-benzene The derivative is further reacted in an uncontrolled manner to provide an unknown secondary product. At −50 ° C., the rate of degradation of the 2,3-difluorophenyllithium derivative is slight, but at −25 ° C., it is explosive (critical temperature: −22.5 ° C.) and the 2,3-difluorophenyllithium derivative is Sudden disassembly
    Similar to ortho-fluoroarylmetal compounds, other ortho-haloarylmetal compounds can also be obtained using ortho-position hydrogens with bases (see, for example, Howeben-Weyl, Methode). der organischen Chemie (Methods of Organic Chemistry), Vol. 13/1, 122-123, Shuttgart 1970).
    However, other ortho-haloarylmetal compounds generally have lower stability than ortho-fluoroarylmetal compounds, which means that the decomposition reactions occur at significantly lower temperatures. See, eg, Bull. Soc. Chim. France 1986 No. 6, 925-929, it is known that the chloroaryl compound metallized at the ortho position readily removes chloride from the exothermic reaction, resulting in the formation of arin and the formation of unwanted byproducts.
    According to German Patent No. 42 19 281, it is also possible to replace the hydrogen atom of the aromatic compound in the ortho position relative to the trifluoromethoxy group. Deprotonation to other groups at the ortho position, such as alkoxy groups, cyano groups, amines and amides, is also described (The Chemistry of the functional groups, Vol. 4, edited by S. Patai). John Wiley & Sons 1987, pages 59-67). Even in these groups, it is generally necessary to maintain a low temperature to avoid secondary reactions.
    Very low temperatures are particularly necessary when the aromatic compound to be deprotonated contains reactive groups such as arylmetal compounds already formed or esters or cyano groups which react with bases used at relatively high temperatures.
    Thus, in order to prevent the alkyllithium compound from being added to the electrophilic group, many of the aromatic compounds capable of reacting as electrophilic reagents, such as benzonitrile, due to the reactive group are desorbed using lithium amides prepared from secondary amines. Preference is given to protonation (see, eg, J. Org. Chem. 47, 2681, 1982). However, deprotonation using the lithium amide for industrial processes is inadequate due to the high cost of the parent compound amine.
    When deprotonating aromatic compounds having only very weak acidic hydrogen atoms, the very low temperatures that must generally be observed for sensitive ortho-substituted arylmetal compounds have proved particularly disadvantageous. These aromatic compounds often require very long reaction times, but can not provide poor yields or deprotonate at all at low temperatures, while secondary reactions occur at high temperatures. Faster deprotonation rates and thus higher yields of arylmetal compounds are often not achieved in the prior art methods even when low temperatures are maintained.
    It is an object of the present invention to find a process for preparing ortho-substituted arylmetal compounds and reacting them with electrophilic reagents, in particular ortho, which can be carried out at an advantageous cost on an industrial scale without the above-mentioned disadvantages of the conventional methods. To find a method of preparing a haloaryl metal compound and reacting the compound with an electrophilic reagent.
    Recently, when the corresponding aromatic compounds are treated with alkyl- or arylmetal compounds or metal hydrides in the presence of catalytic amounts of secondary metal amides, halogen atoms, trifluoromethoxy groups, dialkylamino groups, nitrile groups, alkoxy It has been found that the process for producing an arylmetal compound can be carried out safely and in high yield by deprotonating an aromatic compound having a hydrogen atom in the ortho position relative to the group or dialkylamido group. The ortho-substituted arylmetal compound prepared can be reacted with an electrophilic reagent in a general manner.
    In the process according to the invention, the catalytic amount of secondary amines is converted to the corresponding metal amides using alkyl- or arylmetal compounds or metal hydrides. After deprotonation of each aromatic compound with this metal amide, the modified amine during the reaction is converted back to the metal amide by the alkyl metal or aryl metal compound or metal hydride present. Surprisingly, the use of catalytic amounts of secondary amines increases the rate of deprotonation and yield of arylmetal compounds, but metal amides generally have lower basicities than, for example, alkyllithium compounds.
    According to the process of the invention, it is surprisingly possible to produce lithiated aromatic compounds in high yields in a simple and cost effective manner, which can be used, for example, as useful intermediates for liquid crystals, adjuvants, crop protection compositions and drugs. Using only catalytic amounts of secondary amines only requires a small amount of amines to be removed and disposed of when necessary, reducing costs and simplifying the workup of the reaction mixture.
    Thus, the present invention is characterized in that at least one halogen atom, trifluoromethoxy group, characterized in that the deprotonation of an aromatic compound is carried out using an alkyl- or arylmetal compound or a metal hydride in the presence of a catalytic amount of a secondary metal amide, An ortho-substituted arylmetal compound is prepared by deprotonating an aromatic compound having a hydrogen atom in the ortho position to a dialkylamino group, a nitrilo group, an alkoxy group, or a dialkylamido group to prepare an ortho-substituted arylmetal compound. It provides a method for reacting.
    A preferred subject of the invention is to prepare ortho-substituted arylmetal compounds, characterized in that deprotonation of the aromatic compounds is carried out using alkyl- or arylmetal compounds or metal hydrides in the presence of catalytic amounts of secondary metal amides. And reacting this compound with the corresponding electrophilic reagent to provide a compound of formula
    Where
    Q is F, Cl, CN, OCF 3 , CONR 2 , NR 2 or OR,
    R is alkyl having 1 to 7 carbon atoms,
    R 1 is H, F, Cl, Br, CN; Alkyl, alkenyl, alkoxy, alkenyloxy having up to 18 carbon atoms; Or a mesogenic group,
    W, X and Y are each independently of the other N, CH, CCN, CCl or CF,
    E is ego,
    R 2 is alkyl having 15 or less carbon atoms, alkoxy, alkenyl, alkenyloxy; Or a mesogenic radical corresponding to the R 1 group,
    M is Li, K or Na,
    S is 0 or 1,
    BX 2 is a chemical formula Trioxatriborinone radical,
    Z is Or a group of the formula -B (OR 3 ) (OR 4 ),
    R 3 and R 4 are H; Alkyl, alkenyl or cycloalkyl having up to 10 carbon atoms, or together form an alkylenediyl group of the formula-(CH 2 ) n -or -CH 2 CHR 5 -CH 2- ,
    n is 2, 3 or 4,
    R 5 is alkyl, alkoxy or alkenyl having up to 18 carbon atoms, or a mesogenic radical corresponding to formula (2),
    SI is a trihydrocarbylsilyl group of the formula -Si (R 6 ) 3 ,
    R 6 in each occurrence is independently an aliphatic, cycloaliphatic, araliphatic or aromatic radical,
    TiX 3 is a radical of the formula TiBr 3 , TiCl 3 or Ti (OR 3 ) 3 ,
    ZnX is a radical of ZnBr, ZnCl, ZnR 3 or ZnOR 3 .
    In particular, the present invention provides a process wherein R 1 is a mesogenic group of formula 2:
    R 0 -A 1 -Z 1- (A 2 -Z 2 ) -m
    Where
    R 0 is F, CN; Unsubstituted or monosubstituted alkyl or alkenyl radicals having up to 15 carbon atoms, monosubstituted with CN, halogen or CF 3 , wherein at least one CH 2 group in each case is also independently of each other at each occurrence of -S-, -O-,- May be substituted by CO—, —CO—O—, —O—CO— or —O—CO—O— so that S— and / or O— atoms are not directly connected to each other,
    Z 1 and Z 2 are independently of each other at each occurrence -CH 2 -CH 2- , -C≡C-, -CH 2 O-, -OCH 2- , -CO-O-, -O-CO-,- CH = N-, -N = CH-, -CH 2 S-, -SCH 2- , a single bond, or an alkylene group of 3 to 6 carbon atoms, wherein the -CH 2 -group is -O-, -CO May be substituted by -O-, -O-CO-, -CH halogen- or -CHCN-,
    A 1 and A 2 in each case independently represent (a) a trans-1,4-cyclohexylene radical, in which one or more non-adjacent CH 2 groups can be substituted with -O- and / or -S-, ( b) 1,4-phenylene radicals in which one or two CH groups may be substituted by N, (c) 1,3-cyclobutylene, 1,3-bicyclo (1,1,1) -pen Tylene, 1,4-cyclohexenylene, 1,4-bicyclo (2,2,2) -octylene, piperidine-1,4-diyl, naphthalene-2,6-diyl, decahydronaphthalene- 2,6-diyl and 1,2,3,4-tetrahydronaphthalene-2,6-diyl are radicals selected from the group consisting of: (a) and (b) radicals may be substituted by CN or F,
    m is 0, 1 or 2.
    Ortho-haloaryl derivatives prepared by the process according to the invention include mono-, di-, tri- and tetrahalophenyl derivatives, and pentahalophenyl derivatives.
    Particularly preferred embodiments of the present invention are those wherein the arylmetal compound obtained by metallization is a metal halide (eg ZnCl 2 or ZnBr 2 ) or other metal compound (eg Ti (OR 3 ) 4 , preferably titanium tetraisopro Foxoxide, titanium tetramethoxide, titanium tetraethoxide or titanium tetra-n-propoxide). Compounds obtained by such transition metallization are generally more thermally stable than the starting materials and can likewise react with electrophilic reagents.
    In addition, 2-halopyridin-3-yl derivatives can also be prepared by the process according to the invention. Whether other substituents are present on the aromatic compound in addition to the fluorine substituent is not important for carrying out the process according to the invention. Other substituents that may be mentioned are, for example, alkyl, alkenyl or alkoxy groups, chlorine and bromine or mesogenic groups. Fluorinated aromatic rings may also be components of condensed ring systems such as naphthalene, di- and tetra-hydronaphthalene or 2,3,4,5-tetrahydro-1H-3-benzazine derivatives.
    For simplicity, in the following specification, Phe is a 1,4-phenylene group, wherein one or two CH groups may also be substituted with N, and the 1,4-phenylene group may be substituted with one or two halogen atoms. Where ArF is a chemical formula Is a fluorinated 1,4-phenylene group wherein L 1 , L 2 and L 3 are each independently H or F in each case.
    Cy is a trans-1,4-cyclohexylene radical, wherein one or more non-contiguous CH 2 -groups may also be substituted by -O-.
    E is a group introduced by the process according to the invention.
    Preferred electrophilic reagents are compounds of formulas 3-16:
    R 2 -CHO

    R 2 -CH 2 -X 1
    R 3 -CO-R 4
    (R 2 ) 2 N-CHO
    CO 2
    halogen
    Ti (OR 3 ) 3
    ZnCl 2

    Where
    R 2 is alkyl having 1 to 15 carbon atoms, a mesogenic group corresponding to formula (2), ego,
    m is 1 or 2,
    X 1 is Cl, Br, iodine, toluene or benzenesulfonic acid group, or perfluoroalkyl sulfonic acid group.
    Halogen preferably means F, Cl, Br, I, in particular Br or I. R 3 and S have the same meaning as described above.
    The silylation reagent is a SI-L compound of formula 17, wherein SI is as defined above and L is a leaving group, in particular the compound:
    (CH 3 ) 3 Si-Cl
    (CH 3 ) SiBr
    (CH 3 ) 3 SiI
    (CH 3 ) 3 SiOSO 2 CF 3
    (CH 3 ) 2 (tC 4 H 9 ) SiCl
    (C 6 H 5 ) 2 (tC 4 H 9 ) SiCl
    (C 2 H 5 ) 3 SiCl
    (IC 3 H 7 ) 3 SiCl
    In order to prepare compounds of formula 1 wherein E is B (OR 3 ) (OR 4 ), trialkyl borate of B (OR 3 ) 2 (OR 4 ) of formula 18a is preferably suitable.
    Particular preference is given to using electrophilic reagents of the formulas 3a to 18a for the process according to the invention:








    (CH 3 ) N-CHO

    Formula 17a
    (H 3 C) 3 SiCl
    Formula 17e
    (H 3 C) 2 (tC 4 H 9 ) SiCl
    B (OR 3 ) 2 (OR 4 )
    Where
    R 7 is preferably an alkyl, alkoxy, alkenyl or alkenyloxy radical having up to 12 carbon atoms,
    L 1 , L 2 , L 3 and L 4 are H or F.
    More preferred electrophilic reagents for the process according to the invention are ketones of formula
    Where
    R 8 and R 9 independently of one another are alkyl or alkenyl radicals having up to 15 carbon atoms and unsubstituted or monosubstituted by CN, halogen or CF 3 , in which at least one CH 2 group is independent of each other Can be substituted by -S-, -O-, A, -CO-, -CO-O-, -O-CO- or -O-CO-, whereby the -S- and / or -O- atoms Are not directly coupled to each other.
    A is independently of each other at each occurrence (a) a trans-1,4-cyclohexylene radical in which one or more non-adjacent CH 2 groups can be substituted with -O- and / or -S-, (b) one or 1,4-phenylene radical wherein two CH groups may be substituted by N, c) 1,3-cyclobutylene, 1,3-bicyclo (1,1,1) pentylene, 1,4- Cyclohexenylene, 1,4-bicyclo (2,2,2) octylene and piperidine-1,4-diyl, and the (a), (b) and (c) radicals are R 8 , R 9 , Mono- or polysubstituted by CN or halogen.
    Particularly preferably, the process according to the invention is used to metallize the compounds of the formulas 20a to 20j:





    Where
    Q and R 1 are as defined above,
    L 1 , L 2 , L 3 and L 4 are independently of each other H or F.
    Q 1 is F or Cl, in particular F.
    Preferably, only one of the L 1 and L 2 radicals is H and the other is F.
    Compounds of formula I prepared according to the present invention include compounds of formulas 21-29:




    Of the above compounds, the compounds of the formulas 21, 22, 24 and 27 are particularly preferred. In the compounds of Formulas 21 to 27, R 1 is preferably H; In each case alkyl or alkoxy having 1 to 12 carbon atoms; Or a mesogenic radical, wherein R 1 is H or alkoxy having 1 to 12 carbon atoms, especially 2 to 4 carbon atoms.
    Compounds of formulas 22, 25, 26, and 27 for preparing liquid crystals having 2,3-difluoro-1,4-phenylene or 2,3-difluoro-1,4-phenyleneoxy structural units Particularly suitable as intermediate. Compounds of formula (I) having mesogenic radicals of compounds of formula (2) include preferred compounds of formulas (30) to (42):
    R 0 -A 1 -ArF-E
    R 0 -A 1 -Z 1 -ArF-E
    R 0 -A 1 -A 2 -ArF-E
    R 0 -A 1 -A 2 -Z 2 -ArF-E
    R 0 -A 1 -Z 1 -A 2 -ArF-E
    R 0 -A 1 -Z 1 -A 2 -Z 2 -ArF-E
    R 0 -A 1 -A 2 -A 2 -ArF-E
    R 0 -A 1 -Z 1 -A 2 -A 2 -ArF-E
    R 0 -A 1 -A 2 -Z 2 -A 2 -ArF-E
    R 0 -A 1 -A 2 -A 2 -Z 2 -ArF-E
    R 0 -A 1 -Z 1 -A 2 -Z 2 -A 2 -ArF-E
    R 0 -A 1 -Z 1 -A 2 -A 2 -Z 2 -ArF-E
    R 0 -A 1 -A 2 -Z 2 -A 2 -Z 2 -ArF-E
    Among the above compounds, the compounds of the formulas 30, 31, 32, 33 and 36 are particularly preferred.
    Among the compounds of formula 30, compounds of formula
    Among the compounds of the formula (31), compounds of the formula are particularly preferred:
    The following compound groups include particularly preferred compounds of the formulas 43 to 57 which can be prepared by the process according to the invention:







    Where
    R 1 , R 7 , BX 2 and Si have the above meanings.
    L 1 , L 2 and L 3 are independently of each other H or F.
    Preferably, secondary metal amides are used which are used in catalytic amounts by reaction with the corresponding alkyl- or arylmetal compound or metal hydride from secondary amines of the formula 58 or 59:

    Where
    R 10 and R 11 are alkyl or cycloalkyl having 1 to 15 carbon atoms; Aryl, trimethylsilyl or triethylsilyl,
    R 12 is H, OH; Alkoxy or cycloalkoxy having 1 to 15 carbon atoms; Trimethylsilyloxy or triethylsilyloxy,
    r is 0, 1 or 2, preferably 1.
    R 13 and R 14 are H; Alkyl having 1 to 5 carbon atoms; Or aryl, preferably H; Alkyl having 1 to 3 carbon atoms, particularly preferably H, methyl, ethyl or n-propyl.
    R 10 and R 11 are preferably alkyl having 1 to 10 carbon atoms; Cycloalkyl or trimethylsilyl, in particular methyl, ethyl, n-propyl, n-butyl, isopropyl, 2-butyl (= 1-methylpropyl), isobutyl (= 2-methylpropyl), tert-butyl, 2 -Methylbutyl, isopentyl (= 3-methylbutyl), 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylhexyl, 5-methylhexyl, 2-propylpentyl, 6-methylheptyl, 7 Methyloctyl or trimethylsilyl.
    R 12 is preferably H, OH; Alkoxy having 1 to 3 carbon atoms; Or trimethylsilyloxy.
    Preference is given to compounds of the formula 58 in which R 10 and R 11 are identical. Preferred are compounds of formula 59, wherein R 13 and R 14 are identical.
    In preferred compounds of the above and the following formulae, R 1 and R 2 are independently of each other an alkyl group having 1 to 10 carbon atoms; Preferably it is an alkoxy, alkenyl group or alkenyloxy group having in each case 1 to 10 carbon atoms.
    Particularly preferred alkyl groups are n-hexyl, n-pentyl, n-butyl, i-butyl, propyl, i-propyl, methyl and ethyl, especially methyl; Particularly preferred alkoxy groups are n-hexoxy, n-pentoxy, n-butoxy, i-butoxy, n-propoxy, i-propoxy, methoxy and ethoxy, in particular methoxy; Particularly preferred alkenyl groups are hexenyl, pentenyl, butenyl and allyl.
    In preferred compounds of the above and the following formulae, the alkyl radicals in which the CH 2 group (alkoxy or oxaalkyl) can also be substituted with oxygen atoms can be linear or branched. These are preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and therefore preferably ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, propoxy, e. Methoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy or deoxy, and also undecyl, dodecyl, undecoxy, dodecoxy, 2-oxapropyl (= 2-methoxypentyl ), 2-, 3- or 4-oxapentyl, 2-, 3-, 4- or 5-oxhexyl, 2-, 3-, 4-, 5- or 6-oxaheptyl.
    A 1 and A 2 are preferably Cyc or Phe. In the compounds of the above formulas below, Phe is preferably a 1,4-phenylene group (Ph), a 1,4-phenylene group (PheX), pyrimidine-2,5 mono- or disubstituted with F or CN -Diyl group (Pyr), pyridine-2,5-diyl group (Pyn), pyrazine-3,6-diyl group or pyridazine-2,5-diyl group, particularly preferably Ph, PheX, Pyr or Pyn . The compounds produced by the process according to the invention preferably contain up to one 1,4-phenylene group in which one or two CH groups are substituted by N. Cyc is preferably a 1,4-cyclohexylene group. However, particularly preferred are 1,4-cyclohexylene groups in which one of the A 1 and A 2 groups is substituted by CN or F in the 1- or 4-position and the nitrile group or fluorine atom is in the axial position, ie A 1 or A group of 2 A compound of formula 1 having a structure.
    Especially preferred are the formulas (1) and the compounds accordingly having the -Phe-Phe- configuration. -Phe-Phe- is preferably -Ph-Ph-, Pyr-Phe or Ph-Pyn. Especially preferred group, Group, also 4,4'-biphenylyl, unsubstituted or mono- or polysubstituted by fluorine.
    Particular preference is given to the following general formula (1) and compounds belonging thereto which contain a 2,3-difluoro-1,4-phenylene group.
    The Z 1 and Z 2 groups in each case independently of one another are preferably single bonds, secondary preferably -C≡C- or -CH 2 -CH 2 -groups. Particular preference is given to compounds of the formula wherein the Z 1 group is -CH 2 CH 2- . The above compounds of formula (I) and below having branched side R 1 groups may be important. Branched groups of this type generally contain up to two chain branches. R 1 preferably has a straight chain group or a branched group and has no more than one chain branch.
    Preferred branched radicals are isopropyl, 2-butyl (= 1-methylpropyl), isobutyl (= 2-methylpropyl), tert-butyl, 2-methylbutyl, isopentyl (= 3-methylbutyl), 2 -Methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylhexyl, 5-methylhexyl, 2-propylpentyl, 6-methylheptyl, 7-methyloctyl, isopropoxy, 2-methylpropoxy, 2 -Methylbutoxy, 3-methylbutoxy, 2-methylpentoxy, 3-methylpentoxy, 2-ethylheptoxy, 1-methylhexoxy, 1-methylheptoxy, 2-oxa-3-methylbutyl, 3-oxa-4-methylpentyl.
    The R 1 radical may also be an optically active organic radical containing asymmetric carbon atoms. The asymmetric carbon atom is then preferably two differently substituted carbon atoms, H atoms; And fluorine, in each case alkyl or alkoxy having 1 to 5 carbon atoms, and a substituent selected from the group consisting of CN.
    Of the compounds of the above formulas below, compounds in which at least one of the radicals present have one of the preferred meanings are preferred.
    Compounds of the formula 20, wherein Q, R 1 , W, X and Y are as defined above, which are required as starting materials are known or are known under the known reaction conditions suitable for the reaction (e.g. Prepared by a method known per se, as described in Ben-Vale, Methods der organischen Chemie (Methods of Organic Chemistry, Georg-Thieme-Verlag, Shuttgart):
    In addition, variations that are known per se but not discussed in detail herein may also be used.
    Metal alkoxides prepared during the reaction of arylmetal compounds with electrophilic reagents such as ketones, aldehydes or oxiranes can be worked up under aqueous conditions to give the corresponding alcohols, which alcohols can be further treated by known methods. Can be. Likewise, metal alkoxides can be further treated by known methods.
    Other possible uses for the compounds prepared by the process according to the invention are described, for example, in European Patent Publication No. 440 082.
    The following schemes provide further desirable treatment possibilities:

    A method according to the invention for preparing ortho-substituted aryllithium compounds, arylpotassium compounds or arylsodium compounds and reacting these compounds with an electrophilic reagent, in particular for preparing ortho-substituted aryllithium compounds and electrophiles with these compounds Preference is given to a process according to the invention for reacting a sex reagent.
    The reaction procedure of the process according to the invention is simple, first of which the ortho-substituted arylmetal compound preferably has a corresponding aromatic at -100 to + 100 ° C, preferably at -80 to + 40 ° C, in particular at -35 to 0 ° C. Prepared by reacting a compound with a catalytic amount of secondary amine with an alkyl- or arylmetal compound or metal hydride. The prepared ortho-substituted arylmetal compound is then reacted with the electrophilic reagent, preferably at the same or higher temperature.
    Preferably, the molar ratio of aromatic compound to be deprotonated to alkyl- or arylmetal compound or metal hydride is from 1: 1 to 1: 5, preferably from 1: 1 to 1: 2, in particular from 1: 1 to 1: 1.2. A catalytic amount of amine preferably means 0.1 to 90 mol%, in particular 0.2 to 30 mol%, very particularly preferably 1 to 15 mol%, based on the compound to be deprotonated. The ortho-substituted arylmetal compound formed preferably reacts with an excess of electrophilic reagent. The molar ratio of such arylmetal compounds to electrophilic reagents is particularly preferably 1: 1 to 1:10, preferably 1: 1 to 1: 2.
    Starting materials, i.e., aromatic compounds to be metallized, alkyl- or arylmetal compounds or metal hydrides, and also electrophilic reagents and secondary amines, are preferably strong bases such as ethers such as diethyl ether, tetrahydrofuran or methyl Tert-butyl ether), a hydrocarbon (e.g., pentane, hexane, heptane, benzene, toluene, xylene or cyclohexane) or in an inert solvent which is typically suitable for reaction with a mixture of said solvents. These solvents may also be mixed with cosolvents such as hexamethylphosphoramide (HMPT), tetramethylethylenediamine (TMEDA), dimethylpropyleneurea (DMPU) or crown ethers such as 18-crown-6. The amount of solvent is not critical and generally 100 to 1000 G of solvent can be used per mole of compound to be dissolved.
    The alkyl- or arylmetal compounds used are preferably lithium compounds which are generally customary in organic chemistry (see, eg, Modern Synthetic Reactions, 2nd Ed., Benjamin 1972, 547). Particularly suitable alkyl- and aryllithium compounds are n-butyllithium, secondary-butyllithium, tert-butyllithium, methyllithium, ethyllithium, n-propyllithium, i-propyl-lithium, hexyllithium or phenyllithium. However, it is also possible to use all other known alkyl- and aryllithium compounds not specifically mentioned herein. Alkyllithium compounds are preferred. However, it is also possible to use other alkyl- and arylmetal compounds such as, for example, phenyl sodium or phenyl potassium. Alkyl- and aryllithium compounds are preferred, but preferably alkylpotassium compounds prepared in situ from potassium tert-butoxide and alkyllithium can likewise be used (Angew. Chem. Int. Ed. Engl. 12 , 508, 1973). The use of additional stoichiometry or lower potassium tert-butoxide often increases the reaction rate and reaction yield. Potassium tert-butoxide is preferably used in a molar ratio of 1: 100 to 1: 1, in particular 1:50 to 1: 1, relative to the aromatic compound to be deprotonated.
    Suitable metal hydrides are preferably potassium hydride and sodium hydride.
    In the case of preparing aryllithium compounds substituted by the process according to the invention, it is preferred to use alkyllithium for deprotonation. If an aryl potassium compound is to be prepared, it is preferred to use an alkyllithium compound in the presence of potassium tert-butoxide or potassium hydride for deprotonation. If the arylsodium compound is to be prepared, it is preferable to use sodium hydride.
    For the process according to the invention, catalytic amounts of secondary amines, preferably diisopropylamine, piperidine, pyrrolidine or 2,2,6,6-tetramethylpiperidine, 2,2,6,6 Tetramethyl-4-methoxy-piperidine, 2,2,6-6-tetramethyl-4-silyloxypiperidine, 2,2,6,6-tetramethylpiperidineol, 2,2, 5,5-tetramethyl-pyrrolidine or bis (trimethylsilyl) amine is used, which is converted to the corresponding metal amide by addition of an alkyl- or arylmetal compound. After deprotonation of the ortho-substituted aromatic compound with the metal amide, the modified amine is converted back to the metal amide by the alkyl- or arylmetal compound present during the reaction. The amine can be added to the metal compound or other aromatic compound to be deprotonated. Preference is given to adding to the aromatic compound to be deprotonated.
    The use of catalytic amounts of amines increases the yield and rate of deprotonation of ortho-substituted arylmetal compounds.
    For the process according to the invention for producing arylmetal compounds by deprotonation, preference is given to using aromatic compounds having hydrogen atoms in the ortho position relative to fluorine or chlorine atoms or to trifluoromethoxy groups.
    It is also possible to carry out the process according to the invention in order to metallize the aromatic compounds in a continuous flow reactor. This also applies to subsequent reactions with electrophilic reagents. Because of this, the prepared ortho-substituted arylmetal compound can be continuously reacted with a suitable electrophilic reagent.
    The process according to the invention can be carried out in a manner similar to the process described, for example, in European Patent Publication 440 082 B1 and German Patent Publication 42 01 308 C1. For this purpose, electrophilic reagents, aromatic compounds and secondary amines are preferably initially introduced so that alkyl- or arylmetal compounds or metal hydrides are added at room temperature. The intermediate ortho-substituted arylmetal compound is immediately eliminated in situ by the corresponding electrophilic reagent, thus preventing the accumulation of unstable components. Adding catalytic amounts of secondary amines often results in increased yields compared to the methods described herein.
    Suitable electrophilic reagents are preferably compounds of the formulas 2-18, preferably cyclohexanone, such as 4-alkyl-, alkoxy-, alkenyl-, alkenyloxy- or cycloalkylcyclohexanone or 4-aryl Cyclohexanone, or other simple aliphatic or unsaturated ketones such as acetone, butanone, 2-pentanone, methyl vinyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, methyl isobutyl ketone, ethyl isopropyl Ketones, diisopropyl ketones, ethyl isobutyl ketones, isobutyl isopropyl ketones, 2-heptanone, 3-heptanone, 4-heptanone, diisobutyl ketone, methyl vinyl ketone, mesylyl oxide, acetonyl acetone, Benzylidene Acetone, Dibenzal Acetone, Pinacolone, Ethyl Tert-Butyl Ketone, Phenyl Acetone, Acetophenone, Benzophenone, Menton, Poron, Ketoglutar Ester, Lebulin Ester, Diacetone Acrylamide, Isometadon, Nomethetadon , Capital Ionone, ionone, dipiphanone, norpiphanone, teprenon, hygreen, cuscohaigreen, 3-indolyl acetate, phenadoxinone, nabumethone or solanone, n-alkyl halides having 1 to 16 carbon atoms, in particular n-alkyl bromide and iodide such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or nonyl bromide or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or nonyl iodide ), N-alkanals having 2 to 16 carbon atoms, in particular acetaldehyde, propionaldehyde, butyraldehyde, pentanal, hexanal, heptanal, octanal or nonanal, oxirane (e.g. oxirane, 2-methyloxy Column, 2-ethyloxirane, 2-propyloxirane, 2-butyloxirane, 2-pentyloxirane, 2-hexyloxirane or 2-heptyloxirane).
    Suitable silylating agents are compounds of formula 17, preferably trialkylsilyl halides, in which the alkyl group is linear or branched and having 1 to 8 carbon atoms, in particular compounds of formulas 17a to 17h.
    Suitable trialkyl borates are generally compounds of the formula B (OR 3 ) 2 (OR 4 ), preferably B (OR 3 ) 3 , wherein R 3 is preferably methyl, ethyl, propyl, butyl or isopropyl And especially methyl or isopropyl.
    In a preferred embodiment of the process according to the invention, the deprotonation of the halo- or trifluoromethoxy aromatic compound is first carried out by 1 to 50 mole%, in particular 2 to 20 mole, of secondary amines which can first be converted to metal amides by deprotonation. By adding% to the solution of the aromatic compound, it is then introduced into the continuous flow reactor in a stream of defined mass or volume. The base used is preferably a solution of an alkyllithium compound, which is preferably a mass or volume stream containing the base to aromatic compound in a molar ratio of 1: 1 to 1: 2, preferably 1: 1 to 1: 1.2. Is introduced into the continuous flow reactor. In this process, the intermediate formed from the added amine is the corresponding lithium amide which deprotonates the halo- or trimethoxy aromatic compound and is then converted back to the amide by further alkyllithium. After a reaction zone sufficient for full lithiation of the aromatic compound, the solution of the electrophilic reagent is used to convert the electrophilic reagent to the metallized aromatic compound from 1: 1 to 1: 0.5, preferably from 1: 1 to 1: 0.8. It is introduced into the continuous flow reactor in a stream of mass or volume containing in molar ratio. After the electrophilic reagent passes through an additional reaction zone where it reacts with the arylmetal compound, the product stream exits the continuous flow reactor.
    Post-treatment of the reaction mixture and isolation of the product are carried out in a customary manner, for example when ketones, aldehydes or epoxides are used as electrophilic reagents, water and / or reaction mixtures comprising the corresponding metal alkoxides as products The product is isolated in each alcohol form by distillation or crystallization after pouring into ice or dilute acid followed by removal of the aqueous phase.
    When amides are used as electrophilic reagents, the corresponding metallized hemiaminols are first formed which are fragmented into their respective aldehydes after protonation.
    The following examples are intended to illustrate the invention without limiting the invention. Above and below the percentages are percentages by weight. All temperatures are given in degrees Celsius. M.p. is the melting point. Unless stated otherwise, in each case 1.0 to 1.2 equivalents of electrophilic reagent (based on the aromatic compounds used) were used in the examples.
    "Typical post-treatment" means the addition of water if necessary, the mixture is extracted with methylene chloride, diethyl ether or toluene, the organic phase is separated off, dried and evaporated, and the product distilled under reduced pressure, crystallization and / or Or purification by chromatography.
    The following abbreviations are used:
    THF: Tetrahydrofuran
    KOtBu: Potassium tert-butoxide
    RT: room temperature
    MTBE: methyl tert-butyl ether
    Example 1
    1.1 kg / h of a 2,3-difluorophenetol 1M solution containing 10 mol% of 2,2,6,6-tetramethylpiperidine was introduced into a continuous flow reactor and hexyllithium in hexane at -35 ° C. Mix with 0.4 kg / h of 2.5 M solution. After passing the mixture through the reaction zone, 0.28 kg / h of a benzaldehyde 4.7 M solution in THF was added and mixed. After the reaction was completed, the product was collected and worked up in a conventional manner to afford 2,3-difluoro-4-ethoxy-α-phenylbenzyl alcohol. The conversion was 97% based on the starting compound.
    Example 2
    2,3-difluoroethoxybenzene was mixed with n-hexyl lithium in a tubular reactor at −30 ° C. and reacted with benzaldehyde after a residence time of about 15 minutes. 10 mol% of 2,2,6,6-tetramethylpiperidine was added to the aromatic compound to increase the conversion from about 86% to 99%.
    Example 3
    2,3-difluoroethoxybenzene and 10 mol% of 2,2,6,6-tetramethyl-4-piperidinol were stirred with n-hexyl lithium for 15 minutes at about -65 ° C, followed by benz Reacted with aldehydes. The conversion was over 99%.
    Example 4
    2,3-difluorotoluene and 10 mol% of 2,2,6,6-tetramethylpiperidine are mixed with n-hexyl lithium in a tubular reactor at about -30 ° C and after a residence time of about 15 minutes Reacted with benzaldehyde. The conversion rate was about 96%.
    Example 5
    2,3-difluorotoluene was stirred with n-hexyllithium at about −65 ° C. for 1 hour and then reacted with 4- (4-ethylcyclohexyl) cyclohexanone. After water was isolated and removed, the alkene was purified by crystallization. 10 mol% of 2,2,6-6-tetramethylpiperidine was added to the aromatic compound to increase the yield from 72% to 76%.
    Example 6
    1,2-difluorobenzene and 10 mol% of 2,2,6,6-tetramethylpiperidine were stirred with n-hexyllithium at about −65 ° C. for 15 minutes and then reacted with benzaldehyde. The conversion was about 95%.
    Example 7
    3- (4-propylcyclohexyl) fluorobenzene was stirred with n-hexyllithium at about −70 ° C. for 1 hour and reacted with trimethylsilyl chloride. Only 12% conversion was achieved by adding 10 mol% of 2,2,6,6-tetramethylpiperidine, while 50 mol% of 2,2,6,6-tetramethylpiperidine and 50 mol% of KOtBu were added. The addition increased to 92% when added.
    The following compounds are obtained in a similar manner by the process according to the invention using the corresponding precursors.
    Examples 8-11
    Examples 12-28
    Examples 29-34
    (29) 4-n-propyl-2,6-difluorobenzeneboronic anhydride
    (30) 4- (4-propylcyclohexyl) -2,3-difluorobenzeneboronic anhydride
    (31) 4-propyl-2,3-difluorobenzeneboronic anhydride
    (32) 4- (4-ethylphenyl) -2,3-difluorobenzeneboronic acid anhydride
    (33) 4- (2- (4- (4-propylcyclohexyl) cyclohexyl) ethyl) -2,3-difluorobenzeneboronic anhydride
    (34) 4-ethoxy-2,3-difluorophenylboronic anhydride
    Example 35
    3,5-difluoro (4-propylcyclohexyl) benzene and 2 mol% of 2,2,6,6-tetramethylpiperidine are mixed with n-hexyl lithium in a tubular reactor at -50 ° C, and After 10 minutes of residence time, the reaction was carried out with N-formylpiperidine. The conversion was over 98%.
    According to the present invention it is possible to produce ortho-haloarylmetal compounds in high yield at an advantageous cost on an industrial scale without having the above-mentioned disadvantages of the conventional methods, and the compounds thus prepared are reacted with an electrophilic reagent to produce the final product. Can be obtained.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] Characterized by deprotonating an aromatic compound using an alkylmetal compound, an arylmetal compound or a metal hydride in the presence of a catalytic amount of a secondary metal amide,
    Ortho-substituted arylmetals by deprotonating aromatic compounds having hydrogen atoms at the ortho position to one or more halogen atoms, trifluoromethoxy groups, dialkylamino groups, nitrilo groups, alkoxy groups or dialkylamido groups A method of preparing a compound and reacting the compound with an electrophilic reagent.
    [2" claim-type="Currently amended] The method of claim 1,
    A process for preparing an ortho-haloarylmetal compound and reacting the compound with an electrophilic reagent.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    A process for preparing ortho-substituted aryl lithium compounds, aryl potassium compounds, and aryl sodium compounds and reacting these compounds with electrophilic reagents.
    [4" claim-type="Currently amended] Characterized by deprotonating an aromatic compound using an alkylmetal compound, an arylmetal compound or a metal hydride in the presence of a catalytic amount of a secondary metal amide,
    Ortho-substituted arylmetal compounds by deprotonating an aromatic compound having a hydrogen atom in the ortho position relative to one or more halogen atoms, trifluoromethoxy groups, dialkylamino groups, nitrile groups, alkoxy groups, or dialkylamido groups To prepare a compound and react with the corresponding electrophilic reagent to provide a compound of formula
    Formula 1

    Where
    Q is F, Cl, CN, OCF 3 , CONR 2 , NR 2 or OR,
    R is alkyl having 1 to 7 carbon atoms,
    R 1 is H, F, Cl, Br, CN; Alkyl, alkenyl, alkoxy, alkenyloxy, each having 18 or less carbon atoms; Or a mesogenic group,
    W, X and Y are each independently of each other N, CH, CCN, CCl or CF,
    E is ego,
    R 2 is alkyl having 1 to 15 carbon atoms, alkoxy, alkenyl, alkenyloxy; Or a mesogenic radical corresponding to the R 1 group,
    M is Li, K or Na,
    S is 0 or 1,
    BX 2 is a chemical formula Trioxatriborinone radical,
    Z is Or a group of the formula -B (OR 3 ) (OR 4 ),
    R 3 and R 4 are H; Alkyl, alkenyl, or cycloalkyl, each having up to 10 carbon atoms, or together form an alkylenediyl group of the formula-(CH 2 ) n -or -CH 2 CHR 5 -CH 2- ;
    n is 2, 3 or 4,
    R 5 is alkyl, alkoxy or alkenyl having up to 18 carbon atoms, or a mesogenic radical corresponding to formula (2),
    SI is a trihydrocarbylsilyl group of the formula -Si (R 6 ) 3 ,
    R 6 in each occurrence is independently an aliphatic, cycloaliphatic, araliphatic or aromatic radical,
    TiX 3 is a radical of the formula TiBr 3 , TiCl 3 or Ti (OR 3 ) 3 ,
    ZnX is a radical of ZnBr, ZnCl, ZnR 3 or ZnOR 3 .
    [5" claim-type="Currently amended] The method of claim 4, wherein
    Wherein R 1 is a mesogenic group of formula:
    Formula 2
    R 0 -A 1 -Z 1- (A 2 -Z 2 ) -m
    Where
    R 0 is F; At least 15 carbon atoms and at least one CH 2 group is unsubstituted or monosubstituted by CN, halogen or CF 3 and independently from each other at each occurrence is -S-, -O-, -CO-, -CO-O-,- Are alkyl or alkenyl radicals which may be substituted by O-CO- or -O-CO-O- so that the S- and / or O- atoms are not directly connected to each other,
    Z 1 and Z 2 are independently of each other at each occurrence -CH 2 CH 2- , -C≡C-, -CH 2 O-, -OCH 2- , -CO-O-, -O-CO-, -CH ═N—, —N═CH—, —CH 2 S—, —SCH 2 —, a single bond, or an alkylene group having 3 to 6 carbon atoms, wherein the —CH 2 — group is —O—, —CO— O-, -O-CO-, -CH halogen- or -CHCN- can be substituted),
    A 1 and A 2 in each case independently represent (a) a trans-1,4-cyclohexylene radical, in which one or more non-adjacent CH 2 groups may be substituted with -O- and / or -S-, ( b) 1,4-phenylene radicals in which one or two CH groups may be substituted by N, (c) 1,3-cyclobutylene, 1,3-bicyclo (1,1,1) -pen Methylene, 1,4-cyclohexenylene, 1,4-bicyclo (2,2,2) octylene, piperidine-1,4-diyl, naphthalene-2,6-diyl, decahydronaphthalene-2 , 6-diyl and 1,2,3,4-tetrahydronaphthalene-2,6-diyl are radicals selected from the group consisting of: (a) and (b) radicals may be substituted by CN or F,
    m is 0, 1 or 2.
    [6" claim-type="Currently amended] The method according to any one of claims 1 to 5,
    Characterized in that a secondary metal amide is obtained from a secondary amine of the formula
    Formula 58

    Formula 59

    Where
    R 10 and R 11 are alkyl or cycloalkyl having 1 to 15 carbon atoms; Aryl, trimethylsilyl or triethylsilyl,
    R 12 is H, OH; Alkoxy or cycloalkoxy having 1 to 15 carbon atoms; Trimethylsilyloxy or triethylsilyloxy,
    r is 0, 1 or 2,
    R 13 and R 14 are H; Alkyl having 1 to 5 carbon atoms; Or aryl.
    [7" claim-type="Currently amended] The method according to any one of claims 1 to 6,
    To deprotonate an alkyllithium compound, an aryllithium compound, potassium hydride or sodium hydride.
    [8" claim-type="Currently amended] The method according to any one of claims 1 to 7,
    Deprotonation in the presence of potassium t-butoxide.
    [9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
    The starting material is reacted at a temperature of -80 to + 40 ° C.
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    同族专利:
    公开号 | 公开日
    DE19858855A1|2000-06-21|
    JP4481407B2|2010-06-16|
    KR100636466B1|2006-10-18|
    EP1010702B1|2004-07-28|
    EP1010702A3|2002-04-10|
    DE59910061D1|2004-09-02|
    AT272064T|2004-08-15|
    JP2000239282A|2000-09-05|
    EP1010702A2|2000-06-21|
    US6420584B1|2002-07-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-12-19|Priority to DE19858855A
    1998-12-19|Priority to DE19858855.0
    1999-12-17|Application filed by 플레믹 크리스티안, 메르크 파텐트 게엠베하
    2000-10-25|Publication of KR20000062207A
    2006-10-18|Application granted
    2006-10-18|Publication of KR100636466B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE19858855A|DE19858855A1|1998-12-19|1998-12-19|Process for the preparation of ortho-substituted aryl metal compounds and their reaction with electrophiles|
    DE19858855.0|1998-12-19|
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