US20030125549A1 - Process for the catalytic asymmetric disubstitution of carboxamides using 2 different Grignard reagents - Google Patents

Process for the catalytic asymmetric disubstitution of carboxamides using 2 different Grignard reagents Download PDF

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US20030125549A1
US20030125549A1 US10322570 US32257002A US2003125549A1 US 20030125549 A1 US20030125549 A1 US 20030125549A1 US 10322570 US10322570 US 10322570 US 32257002 A US32257002 A US 32257002A US 2003125549 A1 US2003125549 A1 US 2003125549A1
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Herwig Buchholz
Urs Welz-Biermann
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Herwig Buchholz
Urs Welz-Biermann
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023Preparation; Separation; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/66Preparation of compounds containing amino groups bound to a carbon skeleton from or via metallo-organic compounds

Abstract

The invention relates to a method for asymmetrically disubstituting carboxylic acid amides on the geminal carbonyl-C atom using two different grignard reagents in the presence of a metal alcoholate compound used as a catalyst and in the presence of another organometallic compound used as a co-catalyst.

Description

  • The present invention relates to a process for disubstituting carboxamides using 2 different Grignard reagents in the presence of an organometallic compound as catalyst and a further organometallic compound as cocatalyst. [0001]
  • It is already known from the prior art, in particular from the publication in Monatsheften Chem. 93, pages 469 to 475 (1962), that asymmetric alkylated amines are obtained in the reaction of carboxamides such as formamide with two different Grignard reagents. The yield of these products is so low (at most 15%) that these reaction products can only be referred to as byproducts. [0002]
  • Accordingly, it was the object of the invention to prepare asymmetrically substituted amino compounds not only as byproducts in the reaction of carboxamides with 2 different Grignard reagents, but in an acceptable yield and sufficient options for varying the substituents. [0003]
  • Using the process according to the invention, it is possible to prepare asymmetrically substituted amino compounds with a considerably improved yield. [0004]
  • Accordingly, the present invention provides a process for preparing compounds of the general formula (I) [0005]
    Figure US20030125549A1-20030703-C00001
  • in which [0006]
  • R[0007] 1, R2 and R3 independently of one another are H, A, Ar, —Si(R6)3, —Sn(R6)3, —SR7, —OR7, —NR8R9 or R1 and R2 or R1 and R3 or R8 and R9 can be attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to nitrogen, at least one further heteroatom selected from the group consisting of —S—, —O— and —NR6—,
  • R[0008] 4 and R5 are A, Ar, —Si(R6)3, —Sn(R6)3, —SR7, OR7, —NR8R9, in which R8 and R9 are as defined above or R8 and R9 are attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to one nitrogen atom, at least one heteroatom selected from the group consisting of —S—, —O— and —NR6—;
  •  or where two radicals R[0009] 4 are attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to one nitrogen atom, at least one heteroatom selected from the group consisting of —S—, —O— and —NR6,
  •  with the proviso that R[0010] 4 and R5 in the β position may have at most one hydrogen atom in each case,
  • R[0011] 6, R7, R8 and R9 independently of one another are A or Ar,
  • A is a straight-chain or branched alkyl radical having from 1 to 10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10 C atoms, or a straight-chain or branched alkynyl radical having 2-10 C atoms or a substituted or unsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 C atoms, and [0012]
  • Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms, [0013]
  •  characterized in that a compound of the general formula (II) [0014]
    Figure US20030125549A1-20030703-C00002
  • in which R[0015] 1, R1 and R3 have the meanings given above for the formula (I) is reacted with a nucleophilic reagent of the general formula (IIIa) and a nucleophilic reagent of the general formula (IIIb)
  • Z-R4  (IIIa)
  • Z-R5  (IIIb)
  • in which [0016]
  • R[0017] 4 and R5 have the meaning given for the formula (I) and
  • Z is Li or MgX where [0018]
  • X is Hal and [0019]
  • Hal is Cl, Br or I. [0020]
  • According to the invention, the process is carried out in the presence of catalytic amounts of a metal alkoxide of the general formula (VI): [0021]
  • MX4-n(OR)n  (IV)
  • in which [0022]
  • M is titanium, zirconium or hafnium, [0023]
  • X is Cl, Br, I and [0024]
  • R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms [0025]
  • n an integer from 1 to 4. [0026]
  • Preference is given to using metal alkoxides in which R is isopropyl. Particular preference is given to using the metal alkoxide Ti(OiPr)[0027] 4 in which iPr is an isopropyl radical.
  • The present invention also provides a corresponding process which is carried out in the presence of a cocatalyst. Accordingly, the present invention includes a process which is carried out using metal isopropoxides and alkylsilyl halides as cocatalysts; i.e. metal isopropoxides of the general formula (V) and alkylsilyl halides of the general formula (VI) [0028]
  • M′(s+)(O-isopropyl)s  (V)
  • R3SiX  (VI)
  • or of the general formula (VII) [0029]
  • Ro-(X)m—Si—Y—(Si)p-(X)q—Ro  (VII)
  • in which [0030]
  • M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na, [0031]
  • s is an integer from 1 to 4 and is the oxidation stage of the metal, [0032]
  • R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms, [0033]
  • X is F, Cl, Br, CN, [0034]
  • m is 0, 1, [0035]
  • n is 1 to 10, [0036]
  • o is 0, 2, 3, [0037]
  • p is 0, 1 and [0038]
  • q is 0, 1, [0039]
  • with the proviso that o=3 and Y≠(CH[0040] 2)n if m=0.
  • Thus, the invention also provides a process, which is characterized in that [0041]
  • a) a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal alkoxide selected from the group consisting of titanium alkoxide, zirconium alkoxide and hafnium alkoxide and, if appropriate, a cocatalyst are initially charged at room temperature under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, [0042]
  • b) a solution comprising a nucleophilic reagent of the general formula (IIIa) or (IIIb) is added dropwise and [0043]
  • c) the mixture is allowed to react with stirring and, after the reaction has ended, worked up in a customary manner. [0044]
  • Experiments have shown that, using two nucleophilic reagents of the general formulae (IIIa) and (IIIb), which may be Grignard reagents and are added as such to the reaction mixture, it is possible to convert carboxamides of the general formula (II) in the presence of catalytic amounts of titanium alkoxide, zirconium alkoxide or hafnium alkoxide in a simple manner into asymmetrically substituted compounds of the general formula (I). [0045]
  • According to the invention, using the process described herein, it is possible to convert, with good yields, carboxamides of the general formula (II) in which R[0046] 1, R2 and R3 independently of one another can have the following meanings:
  • H or [0047]
  • A i.e. branched or unbranched alkyl having 1-10 C atoms, such as methyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyl having 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and corresponding methyl- or ethyl-substituted cycloalkyl groups, or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched alkenyl having 2 to 10 C atoms, such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl, or [0048]
  • aryl having 6 to 20 C atoms which is either unsubstituted or mono- or polysubstituted, such as phenyl, naphthyl, anthryl, phenanthryl, mono- or polysubstituted by substituents selected from the group consisting of NO[0049] 2, F, Cl, Br, NH2, NHA, NA2, OH and OA, where A can have the meanings given above, can be mono-, poly-, or fully halogenated, preferably fluorinated, or
  • aralkenyl or aralkynyl, where the aryl, alkenyl and alkynyl groups can in each case have the given meanings, sucn as, for example, in phenylethynyl. [0050]
  • Good yields are in particular also obtained using carboxamides in which R[0051] 1 and R2 or R1 and R3 together form a cyclic ring having 3-8 C atoms which, in addition to nitrogen, contains further heteroatoms, such as —S—, —O— or —NR6—. Particular preference is given here to compounds in which R1 and R2 or R1 and R3 form a simple cyclic ring which includes the nitrogen of the carboxamide or in which R1 and R2 or R1 and R3 form a cyclic ring which contains, as further heteroatom, an oxygen atom.
  • Thus, high yields are obtained in this manner when the starting materials used are compounds such as, for example, or [0052]
    Figure US20030125549A1-20030703-C00003
  • The nucleophilic reagent used can be Grignard reagents or organolithium compounds of the general formulae (IIIa) and (IIIb), in which the radicals [0053]
  • R[0054] 4 and R5 are preferably an alkyl radical having 1 to 10 C atoms, such as methyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyl having 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched alkenyl having 2 to 10 C atoms, such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl,
  •  or are an aryl radical having 6 to 20 C atoms which is either unsubstituted or mono- or polysubstituted, such as phenyl, napthyl, anthryl, phenanthryl, mono- or polysubstituted bysubstituents selected from the group consisting of NO[0055] 2, F, Cl, Br, NH2, NHA, NA2, OH and OA, where A can have the meanings given above, can be mono-, poly- or fully halogenated, preferably fluorinated,
  •  or are an aralkyl radical having 7 to 20 C atoms, such as benzyl, optionally mono- or polysubstituted by substituents selected from the group consisting of NO[0056] 2, F, Cl, Br, NH2, NHA, NA2, OH and OA, where A can have the meanings given above, can be mono-, poly- or fully halogenated, preferably fluorinated,
  •  or are an aralkenyl or aralkynyl radical, where the aryl, alkenyl and alkynyl group can in each case have the given meanings, such as, for example, in phenylethynyl. [0057]
  • Furthermore, the radicals R[0058] 4 and RS in the general formulae (IIIa) and (IIIb) can be —Si(R6), —Sn(R6)3, —SR7, —OR7, —NR8R9, in which R6, R7, R8 and R9 independently of one another can have the abovementioned meanings or R3 and R9 are attached to one another and together form a cyclic ring having 3 to 8 C atoms which may optionally, in addition to a nitrogen atom, contain at least one heteroatom selected from the group consisting of —S—, —O— and —NR6—.
  • The radical Z in the general formulae (IIIa) and (IIIb) preferably represents a radical MgX where X is Cl or Br, or the radical Z is lithium. [0059]
  • Particular preference according to the invention is given to using Grignard reagents such as: methylmagnesium bromide, ethylmagnesium bromide, n- or isopropylmagnesium bromide, iso-, sec- or tert-butylmagnesium bromide, n-hexylmagnesium bromide, cyclohexylmagnesium chloride, allylmagnesium bromide, vinylmagnesium bromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, phenylmagnesium bromide, benzylmagnesium chloride, for the reaction. [0060]
  • Furthermore, it was found that only if a cocatalyst is added, the geminal asymmetric dialkylation reactions according to the invention start even at room temperature and result in the complete conversion of the starting materials in a relatively short reaction time. [0061]
  • Suitable cocatalysts for this reaction are metal isopropoxides and alkylsilyl halides. Particularly suitable are metal isopropoxides of the general formula (V) and alkylsilyl halides of the general formula (VI) [0062]
  • M′(s+)(O-isopropyl)s  (V)
  • R3SiX  (VI)
  • or of the general formula (VII) [0063]
  • Ro-(X)m—Si—Y—(Si)p-(X)q—Ro  (VII)
  • in which [0064]
  • M′is Al, Ca, Na, K, Si or Mg, preferably Mg or Na, [0065]
  • s is an integer from 1 to 4 and is the oxidation stage of the metal, [0066]
  • R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms, [0067]
  • X is F, Cl, Br, CN, [0068]
  • m is 0, 1, [0069]
  • n is 1 to 10, [0070]
  • o is 0, 2, 3, [0071]
  • p is 0, 1, and [0072]
  • q is 0, 1, [0073]
  • with the proviso that o=3 and Y≠(CH[0074] 2)n if m=0.
  • Preference is given to using metal isopropoxides in which s is an integer from 1 to 4 and is the oxidation stage of the metal and M′ is Al, Ca, Na, K, Si or Mg. Particular preference is given to Mg or Na. [0075]
  • Preference is given to using alkylsilyl halides in which R is alkyl having 1 to 6 C atoms. Particular preference is given to those in which R is alkyl having 1 to 3 C atoms and X is chlorine. [0076]
  • Particularly suitable cocatalysts are, inter alia, the following silicon compounds: [0077]
  • (CH[0078] 3)3SiCl
  • (CH[0079] 3)2ClSi (CH2)2SiCl (CH3)2
  • (CH[0080] 3)2ClSi (CH2)3CN
  • [(CH[0081] 3)3Si]2O
  • [(CH[0082] 3)3Si]2NH and
  • [(CH[0083] 3)3Si]2.
  • It has been found that the addition of from 0.7 to 1.2 mol, in particular from 0.9 and 1.1 mol, of a cocatalyst based on one mol of starting material leads to improved results such as, for example, higher yields, lower reaction temperature or shorter reaction times. [0084]
  • As can be demonstrated using examples, under favourable conditions a complete conversion of the carboxamide according to the general equation (Eq. 1) has taken place after just one hour: [0085]
    Figure US20030125549A1-20030703-C00004
  • For carrying out the process according to the invention, the catalyst used can be a commercial metal alkoxide selected from the group consisting of titanium alkoxide, zirconium alkoxide and hafnium alkoxide. Preference is given to using titanium tetraisopropoxide. The metal alkoxide, preferably titanium tetraisopropoxide, is used as a solution in a suitable solvent, which is dried beforehand. Suitable solvents are, for example aliphatic or aromatic hydrocarbons or ethers. Preference is given to using solvents selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, which are dried prior to the reaction by methods known to the person skilled in the art. Drying can be carried out with the aid of magnesium sulphate, calcium chloride, sodium, potassium hydroxide or by other methods. [0086]
  • A preferred embodiment of the process according to the invention comprises initially charging the titanium tetraisopropoxide used as catalyst in an amount of from 1 to 15, preferably 1.5 to 14, in particular 2 to 10 and very particularly preferably from 3 to 6 mol %, based on one mol of the amide used as starting material, in the form of a solution adjusted to a temperature of from 10 to 30° C., preferably 15-25° C., particularly preferably to a temperature of about 20° C. Under an atmosphere of inert gas (nitrogen or argon), the starting material, either as such in liquid form or dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, is slowly added dropwise with stirring. An amount of cocatalyst which corresponds to the amount to be reacted is then added dropwise, if required likewise in a solvent. The reaction mixture obtained is stirred for a short period, i.e. for a few minutes, at a constant temperature. Such an amount of the nucleophilic reagent of the general formulae (IIIa) and (IIIb), in particular Grignard reagents, is then slowly added to the resulting reaction mixture that substitution of the geminal carbonyl C atom by two different substituents, i.e. an asymmetric substitution of the geminal carbonyl C atom, can take place. The addition of the nucleophilic reagents according to the invention prepared by methods generally known to the person skilled in the art should take place at such a rate that the temperature of the reaction mixture does not exceed 50° C. It is advantageous to carry out the addition of the nucleophilic reagents, i.e. of the Grignard reagents or the lithium compounds, with efficient mixing, preferably vigorous stirring. To shift the reaction equilibrium to the side of the desired asymmetrically substituted product, the nucleophilic reagents used, preferably Grignard reagents, are each added in amounts of from 0.7 to 1.2 mol per mole of starting material that participates in the reaction. Preference is given to adding the Grignard reagents in amounts of from 0.9 to 1.1 mol, based on 1 mol of starting material. [0087]
  • After the addition of the Grignard reagents has ended, the reaction mixture is stirred for some time at a constant temperature, until the reaction is brought to completion. [0088]
  • If no cocatalyst is added to the reaction mixture, the reaction temperature can, after addition of the nucleophilic reagents has ended and the mixture has been mixed thoroughly, be adjusted to about 80° C., preferably to from 60 to 70° C., in particular to 65° C. [0089]
  • Thus, by the synthesis according to the invention it is possible to prepare asymmetrically substituted amino compounds of the general formula (I) with good or satisfactory yields within adequate reaction times. In an advantageous manner, it is possible, by adding one of the catalysts in combination with one of the cocatalyst compounds described of the general formulae (V), (VI) or (VII), to reduce the reaction times considerably, in the most favourable case to one hour, without this resulting in a reduction in the yields obtained. [0090]
  • Thus, the present invention also provides the use of a catalyst system comprising a metal alkoxide selected from the group consisting of titanium alkoxide, zirconium alkoxide and hafnium alkoxide as catalyst and a compound of the general formulae (V), (VI) or (VII) with the meanings given above, and the use of this catalyst system for preparing the asymmetrically substituted compounds of the general formula (I). [0091]
  • For example, 5 mmol of starting material are, at 20° C. and under an atmosphere of inert gas, added dropwise with stirring to a solution of 3 mol % of titanium tetraisopropoxide in 40 ml of dried tetrahydrofuran. 5 mmol of cocatalyst, likewise taken up in dried tetrahydrofuran, are added slowly with stirring to this mixture. The mixture is stirred at 20° C. for 5 minutes, and a solution of 6 mmol each of two different Grignard reagents is then added at such a rate that the 10 temperature of the reaction mixture does not exceed 50° C. Stirring is continued for one hour, until the reaction has gone to completion. [0092]
  • After the reaction according to the invention, work-up of the reaction mixture can be carried out in a manner known to the person skilled in the art. [0093]
  • Here, the products can be precipitated as salts using solutions of hydrochloric acid, for example a 1 molar ethereal solution of hydrochloric acid, and be filtered off and, if required, purified by recrystallization. [0094]
  • To remove the Lewis acid, it is possible, for example, to add a suitable amount of saturated ammonium chloride 2.5 solution and water, followed by further vigorous stirring for a plurality of hours (1-3 hours). The resulting precipitate is separated off and washed with a little ether, preferably diethyl ether. The filtrate is made alkaline (pH>10) by addition of a suitable base, such as an NaOH, KOH, sodium, carbonate or potassium carbonate solution, preferably sodium hydroxide solution. The phases that are formed are then separated, and the aqueous phase is extracted repeatedly (for example in the special case given above three times with in each case 30 ml) with diethyl ether. The combined organic phases are washed with (for example 15 ml of) saturated sodium chloride solution and can be dried over potassium carbonate, magnesium sulphate or sodium sulphate and filtered. [0095]
  • The products can be purified by various routes using methods known to the person skilled in the art, such as, for example, in the following manner: [0096]
  • 1. They are precipitated as hydrochlorides using 1 M ethereal hydrochloric acid solution and filtered off (the resulting product is, if required, purified by recrystallization). [0097]
  • 2. The organic phase is extracted repeatedly with a 0.5 M acid solution, preferably an aqueous hydrochloric acid solution. The extract obtained is adjusted to pH>10 using bases, preferably 2 M aqueous sodium hydroxide solution, and extracted at least once, preferably repeatedly, with diethyl ether. The resulting organic phases, which contain the reaction product, can be dried, if appropriate, over potassium carbonate, magnesium sulphate or sodium sulphate and be freed from the organic solvent under reduced pressure. [0098]
  • 3. Furthermore, it is possible to isolate the reaction product by removing the organic solvent under reduced pressure and separating the residue that remains by column chromatography, to isolate the reaction product. [0099]
  • In the general description of the process procedure given above, the Grignard reagents can also be replaced by the corresponding lithium compounds. The corresponding lithium compounds, like the Grignard reagents, can be prepared by methods generally known to the person skilled in the art, and they can be reacted according to the invention in the same manner as described above. [0100]
  • The compounds of the general formula (I) prepared according to the invention can be used, for example, as intermediates in the preparation of sulphur- or selenium-containing amines for the chiral catalysis of diethyl zinc syntheses (literature: Werth, Thomas; Tetrahydron Lett. 36; 1995, 7849-7852, Werth, Thomas et al. Helv. Chim. Acta 79, 1996, 1957-1966). [0101]
  • To illustrate and better understand the present invention, examples are given below. However, owing to the general validity of the described principle of the invention, they are not meant to reduce the scope of the present application to just these examples.[0102]
  • EXAMPLES
  • Titanium-tetraisopropoxide-induced asymmetric dialkylation of carboxamides using 2 different Grignard reagents [0103]
  • According to the reaction shown in Equation 1, the following reactions were carried out using one equivalent of (CH[0104] 3)3SiCl as cocatalyst:
    TABLE 1
    Ti(OiPr)4-induced reaction of carboxamides with R4MgX and R5MgX.
    Figure US20030125549A1-20030703-C00005
    R4MgX/ Reaction
    Amide Product Yield R5MgX conditions
    Figure US20030125549A1-20030703-C00006
    Figure US20030125549A1-20030703-C00007
    71% MeMgBr/ PhMgBr 1 h/25° C./ 3 mol % Ti(OiPr)4/5 mmol cocat
    Figure US20030125549A1-20030703-C00008
    Figure US20030125549A1-20030703-C00009
    81% PhMgBr/ BnMgCl 1 h/RT/ 3 mol % Ti(OiPr)4
    Figure US20030125549A1-20030703-C00010
    Figure US20030125549A1-20030703-C00011
    79% MeMgBr/ PhMgBr 3 mol % Ti(OiPr)4/5 mmol cocat

Claims (16)

  1. 1. Process for preparing compounds of the general formula (I)
    Figure US20030125549A1-20030703-C00012
    in which
    R1, R2 and R3 independently of one another are H, A, Ar, —Si(R6)3, —Sn(R6)3, —SR7, —OR7, —NR8R9 or R1 and R2 or R1 and R3 or R8 and R9 can be attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to nitrogen, at least one further heteroatom selected from the group consisting of —S—, —O— and —NR6—,
    R4 and R5 are A, Ar, —Si(R6)3, —Sn(R6)3, —SR7, —OR7, —NR8R9, in which R8 and R9 are as defined above or R8 and R9 are attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to one nitrogen atom, at least one heteroatom selected from the group consisting of —S—, —O— and —NR6—;
     or where two radicals R4 are attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to one nitrogen atom, at least one heteroatom selected from the group consisting of —S—, —O— and —NR6—,
     with the proviso that R4 and R5 in the β position may have at most one hydrogen atom in each case,
    R6, R7, R8 and R9 independently of one another are A or Ar,
    A is a straight-chain or branched alkyl radical having from 1 to 10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10 C, atoms, or a straight-chain or branched alkynyl radical having 2-10 C atoms or a substituted or unsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 C atoms, and
    Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms,
    characterized in that
    a compound of the general formula (II)
    Figure US20030125549A1-20030703-C00013
     in which R1, R2 and R3 have the meanings given above for the formula (I) is reacted with a reagent of the general formula (IIIa) and a nucleophilic reagent of the general formula (IIIb)
    Z-R4  (IIIA) Z-R5  (IIIb)
    in which
    R4 and R5 have the meaning given for the formula (I), and
    Z is Li or MgX where
    X is Hal and
    Hal is Cl, Br or I.
  2. 2. Process according to claim 1, characterized in that it is carried out in the presence of catalytic amounts of a metal alkoxide selected from the group consisting of titanium alkoxide, zirconium alkoxide and hafnium alkoxide.
  3. 3. Process according to claim 1 or 2, characterized in that it is carried out in the presence of a cocatalyst.
  4. 4. Process according to claims 1 to 3, characterized in that it is carried out in the presence of a metal isopropoxide or an alkylsilyl halide cocatalyst.
  5. 5. Process according to claims 1 to 4, characterized in that the cocatalyst used is a metal isopropoxide of the general formula (V) or an alkylsilyl halide of the general formula (VI)
    M′(s+)(O-isopropyl)s  (V) R3SiX  (VI)
    or of the general formula (VII)
    Ro-(X)m—Si—Y—(Si)p-(X)q-Ro  (VII)
    in which
    M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
    s is an integer from 1 to 4 and is the oxidation stage of the metal,
    R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,
    X is F, Cl, Br, CN,
    m is 0, 1,
    n is 1 to 10,
    o is 0, 2, 3,
    p is 0, 1 and
    q is 0, 1,
    with the proviso that o=3 and Y#(CH2)n if m=0.
  6. 6. Process according to one or more of the preceding claims, characterized in that the catalyst used is a metal alkoxide of the general formula (IV)
    MX4-n(OR)n  (IV)
    in which
    M is titanium, zirconium or hafnium,
    X is Cl, Br, I and
    R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,
    n is an integer from 1 to 4.
  7. 7. Process according to the preceding claims, characterized in that
    a) a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal alkoxide selected from the group consisting of titanium alkoxide; zirconium alkoxide and hafnium alkoxide and, if appropriate, the cocatalyst are initially charged at 10-30° C. under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,
    b) a solution comprising two different nucleophilic reagents of the general formulae (IIIa) and (IIIb)
    in which
    R4 and R5 have the meanings given in claim 1 and
    X has the meanings given in the preceding claims
    is added dropwise and
    c) the mixture is allowed to react with stirring and, after the reaction has ended, worked up in a customary manner.
  8. 8. Process according to claim 7, characterized in that process step a) is carried out at a Temperature of from 15 to 25° C.
  9. 9. Process according to claim 7, characterized in that the process step a) is carried out at room temperature.
  10. 10. Process according to one or more of the preceding claims, characterized in that the nucleophilic reagents used are lithium compounds of the general formulae (IIIa) and (IIIb) in which R4 and R5 can have the meanings given in claim 1 or claim 7.
  11. 11. Process according to one or more of the preceding claims, characterized in that the nucleophilic reagents used are compounds of the general formulae (IIIa) and (IIIb) in which R4 and R5 are methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, cyclopentyl, cyclohexyl, allyl, vinyl, phenyl or benzyl.
  12. 12. Process according to one or more of the preceding claims, characterized in that the compound that is reacted is a compound of the general formula (II) in which R1, R2 and R3 independently of one another are H, methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, phenyl or benzyl.
  13. 13. Catalyst system, comprising a metal alkoxide of the general formula (IV)
    MX4-n(ORn)  (IV)
    in which
    M is titanium, zirconium or hafnium,
    X is Cl, Br, I and
    R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms
    and a cocatalyst of the general formula (V), (VI)
    M′(s+)(O-isopropyl)s  (V)
    R3SiX  (VI)
    or of the general formula (VII)
    Ro-(X)m—Si—Y—(Si)p-(X)q—Ro  (VII)
    in which
    M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
    s is an integer from 1 to 4 and is the oxidation stage of the metal,
    R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,
    X is F, Cl, Br, CN,
    m is 0, 1,
    n is 1 to 10,
    o is 0, 2, 3,
    p is 0, 1 and
    with the proviso that o=3 and Y≠(CH2)n if m=0.
  14. 14. Catalyst system according to claim 13, comprising, as cocatalyst, a compound selected from the group consisting of
    Na(OiPr)
    Mg(OiPr)2
    Al(OiPr)3
    (CH3)3SiCl
    (CH3)2ClSi(CH2)2SiCl(CH3)2
    (CH3)2ClSi(CH2)3CN
    [(CH3)3Si]2O
    [(CH3)3Si]2NH and
    [(CH3)3Si]2.
  15. 15. Catalyst system according to claim 13, comprising, as metal alkoxide, titanium tetraisopropoxide.
  16. 16. Use of a catalyst system according to claims 13 to 15 in a process according to one or more of claims 1 to 12.
US10322570 1998-06-18 2002-12-19 Process for the catalytic asymmetric disubstitution of carboxamides using 2 different Grignard reagents Abandoned US20030125549A1 (en)

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DE19827163.8 1998-09-26
US09719823 US6512145B1 (en) 1998-06-18 1999-06-18 Method for the catalytic, asymmetric disubstitution of carboxylic acid amides with two different grignard reagents
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050202119A1 (en) * 2004-03-10 2005-09-15 Donald Ullman Apparatus for enhancing a chewing gum experience
US20060111308A1 (en) * 2004-11-16 2006-05-25 Wendye Robbins Methods and compositions for therapeutic treatment
US20070087977A1 (en) * 2004-11-16 2007-04-19 Wendye Robbins Methods and compositions for treating pain

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050202119A1 (en) * 2004-03-10 2005-09-15 Donald Ullman Apparatus for enhancing a chewing gum experience
WO2005086867A2 (en) * 2004-03-10 2005-09-22 Ulco Toy And Game Company Apparatus for enhancing a chewing gum experience
WO2005086867A3 (en) * 2004-03-10 2006-12-07 Carmine Capone Apparatus for enhancing a chewing gum experience
US20060111308A1 (en) * 2004-11-16 2006-05-25 Wendye Robbins Methods and compositions for therapeutic treatment
US20070087977A1 (en) * 2004-11-16 2007-04-19 Wendye Robbins Methods and compositions for treating pain
US20090076053A1 (en) * 2004-11-16 2009-03-19 Wendye Robbins Methods and compositions for treating pain
US20090088394A1 (en) * 2004-11-16 2009-04-02 Wendye Robbins Methods and compositions for therapeutic treatment

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