KR20010053016A - Method for symmetrically and asymmetrically disubstituting carboxylic acid amides with organotitanates and grignard reagents - Google Patents

Abstract

The present invention relates to a process for disubstituted carboxylic acid amides to adjacent carbonyl C-atoms using Grignard reagents in the presence of organotitanates.

Description

METHOD FOR SYMMETRICALLY AND ASYMMETRICALLY DISUBSTITUTING CARBOXYLIC ACID AMIDES WITH ORGANOTITANATES AND GRIGNARD REAGENTS}

Prior art, in particular, publication in Monatsheften Chem. 93, pages 469-475 (1962), it is known that asymmetric alkylated amines are obtained in the reaction of two different Grignard reagents with carboxamides such as formamide. These products have very low yields (less than 15%) and can only be referred to as byproducts.

In addition, the prior art, in particular, Collect. Czech. Chem. Commun. 1939, 11, 506 and 1959, 24, 110, it is known that symmetric dialkylation of carboxamides with Grignard reagents can provide amines, but their yields are not satisfactory.

The present invention relates to a process for disubstituted carboxamide using Grignard reagent in the presence of an organotitanium compound.

Accordingly, it is an object of the present invention to prepare symmetrically and asymmetrically substituted amino compounds with significantly improved yields by reaction of Grignard reagents with carboxamides.

Using the process according to the invention, amino compounds substituted symmetrically or asymmetrically can be produced in significantly improved yields.

Accordingly, the present invention provides a process for preparing a compound of formula (I) characterized by reacting a compound of formula (II) with a nucleophilic reagent of formula (III):

ZR ⁴

Where

R ¹ , R ² and R ³ are independently of each other H, A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , or -NR ⁸ R ^9, or Or one or more additional heteroatoms selected from the group consisting of -S-, -O- and -NR ^6- , in addition to nitrogen, in which R ¹ and R ² , or R ¹ and R ³ , or R ⁸ and R ⁹ are bonded together; Can optionally form a cyclic ring having 3 to 8 carbon atoms,

R ⁴ and R ⁵ are the same or different and are A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , or -NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined above or R ⁸ and R ⁹ are bonded to each other to optionally add one or more heteroatoms selected from the group consisting of —S—, —O— and —NR ⁶ — in addition to one nitrogen atom; To form a cyclic ring containing 3 to 8 carbon atoms, provided that R ⁴ and R ⁵ in the β-position each have one or less hydrogen atoms,

R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently of each other A or Ar, wherein A is a straight or branched alkyl radical having 1 to 10 carbon atoms, a straight or branched alkenyl radical having 2 to 10 carbon atoms, or 2 carbon atoms. A straight or branched alkynyl radical of 10 to 10, a substituted or unsubstituted cycloalkyl radical of 3 to 8 carbon atoms, or a monounsaturated or polyunsaturated cycloalkyl radical of 3 to 8 carbon atoms, Ar is a substituent of 6 to 20 carbon atoms Or unsubstituted aryl radicals,

Z is Li or MgX, where X is Hal and is Cl, Br or I.

According to the invention, the process of the invention is carried out in the presence of an organotitanate of formula IV:

R ⁵ Tix _3-n (OR) _n

Where

R ⁵ is as defined in the description of Formula I above,

X is Cl, Br or I,

R is alkyl of 1 to 10 carbon atoms or aryl of 6 to 20 carbon atoms,

n is an integer of 1-3.

Preference is given to using organotitanates in which R is isopropyl. Especially preferred is the use of methyl-, phenyl-, cyclopropyl- or p-fluorophenyl-triisopropyl titanate.

Thus, the present invention also

a) The carboxamide of formula (II), and the organotitanate are initially charged in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether under an atmosphere of inert gas at room temperature,

b) dropwise adding a solution comprising the nucleophilic reagent of formula III,

c) reacting the mixture under agitation and post-treatment in a conventional manner after the reaction is over.

Experimentally, by using a nucleophile reagent of formula III (which may be a Grignard reagent or may be added to the reaction mixture as such), the carboxamide of formula II may be prepared in a simple manner in the presence of an organotitanate. It has been found that it can be converted to symmetric or asymmetric substituted compounds.

According to the invention, using the methods disclosed herein, the carboxamides of formula (II) can be converted in good yields, in which R ¹ , R ² and R ³ are independently of each other,

H, or

A, ie branched or unbranched alkyl of 1 to 10 carbon atoms, for example methyl, ethyl, n- or isopropyl, n-, secondary- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl And suitable isomers thereof; Cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and corresponding methyl- or ethyl-substituted cycloalkyl groups; Monounsaturated or polyunsaturated cycloalkyl groups such as cyclopentenyl or cyclopentadienyl; Branched or unbranched alkenyl having 2 to 10 carbon atoms such as allyl, vinyl, isopropenyl, propenyl; Branched or unbranched alkynyl having 2 to 10 carbon atoms such as ethynyl, propynyl; or

Unsubstituted or monosubstituted or polysubstituted aryl having 6 to 20 carbon atoms, such as phenyl, naphthyl, anthryl, or phenanthryl, wherein these are NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA, where A has the above meaning and may be mono- or polysubstituted with substituents selected from the group consisting of mono-, poly- or fully halogenated, preferably fluorinated) ]; or

Aralkenyl or aralkynyl, wherein the aryl, alkenyl and alkynyl groups may in each case have the meaning above, for example phenylethynyl.

In particular, R ¹ and R ² , or R ¹ and R ³ together form a cyclic ring having 3 to 8 carbon atoms (these cyclic rings are in addition to nitrogen an additional heteroatom such as —S—, —O— or —NR ⁶ — It is also possible to obtain good yields by using the carboxamides which form). Particularly preferred in the present invention, R ¹ and R ² , or R ¹ and R ³ form a simple cyclic ring comprising the nitrogen of the carboxamide, or R ¹ and R ² or R ¹ and R ³ are further It is a compound which forms the cyclic ring containing an oxygen atom as a hetero atom.

Thus, when the starting materials used are, for example, the following compounds, high yields are obtained in this manner:

or

The nucleophilic reagents used may be Grignard reagents in combination with organotitanates of formula IV or organolithium compounds of formula III wherein the radicals R ⁴ and R ⁵ in the formula

Preferably alkyl radicals having 1 to 10 carbon atoms, for example methyl, isopropyl, iso- or tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof; Cycloalkyl having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a corresponding methyl- or ethyl-substituted cycloalkyl group; Monounsaturated or polyunsaturated cycloalkyl groups such as cyclopentenyl or cyclopentadienyl; Branched or unbranched alkenyl having 2 to 10 carbon atoms such as allyl, isopropenyl, or propenyl; Or branched or unbranched alkynyl, for example ethynyl, or propynyl, having 2 to 10 carbon atoms; Unsubstituted or monosubstituted or polysubstituted aryl radicals having 6 to 20 carbon atoms, for example phenyl, naphthyl, anthryl or phenanthryl, wherein these are NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA, wherein A has the above meaning and is mono- or polysubstituted with a substituent selected from the group consisting of mono-, poly- or fully halogenated, preferably fluorinated); NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA, where A has the above meaning and may be mono-, poly- or fully halogenated, preferably fluorinated Aralkyl radicals having 7 to 20 carbon atoms optionally substituted with mono or polysubstituted with a substituent selected from the group consisting of benzyl; Or an aralkenyl or aralkynyl radical, wherein the aryl, alkenyl and alkynyl groups may in each case have the meaning given above, for example phenylethynyl.

In addition, the radicals R ⁴ and R ⁵ in Formula III and Formula IV may be -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , or -NR ⁸ R ⁹ , Wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently of each other as defined above or R ⁸ and R ⁹ are bonded to each other and together form —S—, —O— and —NR ⁶ — in addition to the nitrogen atom; To form a cyclic ring having 3 to 8 carbon atoms which may optionally contain one or more heteroatoms selected from the group.

The radical Z in formula III preferably represents the radical MgX, wherein X is Cl or Br or is lithium.

Particularly preferred according to the invention are, for the reaction, Grignard reagents such as methylmagnesium bromide, isopropylmagnesium bromide, iso- or tert-butylmagnesium bromide, cyclopropylmagnesium bromide, cyclohexylmagnesium chloride, allylmagnesium Bromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, phenylmagnesium chloride and p-fluorophenyl magnesium bromide.

As can be demonstrated using the examples, complete conversion of the carboxamide according to Scheme 1 occurred under favorable conditions:

In order to carry out the process according to the invention, prior to use, organotitanate, preferably organotitanium triisopropoxide, is used as a solution of a suitable solvent. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons or ethers. Preference is given to using a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, dried prior to the reaction by methods known to those skilled in the art. Drying can be performed using magnesium sulfate, calcium chloride, sodium, potassium hydroxide or by other methods.

Preferred embodiments of the process according to the invention comprise organotitanium triisopropoxide in an amount of from 0.7 to 1.3 equivalents, preferably from 0.9 to 1.1 equivalents, based on 1 mole of amide used as starting material Initially filling in the form of a solution adjusted to a temperature of preferably 15 to 25 ° C, particularly preferably about 20 ° C. The starting material is slowly added dropwise with stirring under the atmosphere of an inert gas (nitrogen or argon) in its own liquid form or dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether. do. The reaction mixture obtained is stirred for a short period of time, ie for several minutes at constant temperature. This amount of nucleophilic reagent, in particular Grignard reagent, is then added slowly to the resulting reaction mixture, whereby substitution by two identical or different substituents of adjacent carbonyl C atoms, ie adjacent carbonyl C atoms Symmetric or asymmetric substitution of may occur. The addition of the nucleophilic reagents according to the invention prepared by methods generally known to those skilled in the art should be carried out at a rate such that the temperature of the reaction mixture does not exceed 50 ° C. The addition of the nucleophilic reagent, ie Grignard reagent or lithium compound, is advantageously carried out under efficient mixing, preferably with vigorous stirring. To transfer the reaction equilibrium toward the desired symmetrical or asymmetrically substituted product, the nucleophilic reagent used, preferably Grignard reagent, is added in an amount of 0.7 to 1.3 moles per mole of starting material involved in the reaction. . It is preferable to add the Grignard reagent in an amount of 0.9 to 1.1 moles based on 1 mole of the starting material while the same amount as the organotitanate.

After completion of the Grignard reagent addition, the reaction mixture is stirred for a while until the reaction is complete at constant temperature.

Thus, the synthesis according to the invention makes it possible to prepare symmetrically and asymmetrically substituted amino compounds of the formula (I) in good or satisfactory yields within suitable reaction times.

For example, under an atmosphere of 20 ° C. and an inert gas, 5 mmol of the starting material is added dropwise to a solution of 5.5 mmol of organotitanium triisopropoxide in 40 ml of dried tetrahydrofuran. The mixture is stirred at 20 ° C. for 5 minutes and then a solution of 5.5 mmol of Grignard reagent is added at a rate such that the temperature of the reaction mixture does not exceed 50 ° C. Stirring is continued until the reaction is complete.

After the reaction according to the invention, the reaction mixture can be worked up in a manner known to the person skilled in the art.

In the present invention, the product can be precipitated as a salt using a hydrochloric acid solution, for example a 1 mole etheric solution of hydrochloric acid, filtered and optionally purified by recrystallization.

To remove the Lewis acid, for example, an appropriate amount of saturated ammonium chloride solution and water can be added, followed by further vigorous stirring for several hours (1-3 hours). The resulting precipitate is filtered off and washed with a small amount of ether, preferably diethyl ether. The filtrate is made alkaline (pH> 10) by addition of a suitable base such as NaOH, KOH, sodium carbonate or potassium carbonate solution, preferably sodium hydroxide solution. The formed phases are then separated and the aqueous phase is extracted repeatedly with diethyl ether (for example 3 times or more with 30 ml in each case in the special case given above). The organic phases can be combined, washed with saturated sodium chloride solution (eg 15 ml), dried over potassium carbonate, magnesium sulfate or sodium sulfate and filtered.

The product can be purified by various routes using methods known to those skilled in the art, for example, in the following manner:

1. Precipitate the product as hydrochloride using 1 M etheric hydrochloric acid solution and filter (the resulting product is optionally purified by recrystallization).

2. The organic phase is extracted repeatedly with a 0.5 M acid solution, preferably with an aqueous hydrochloric acid solution. The extract obtained is adjusted to pH > 10 using a base, preferably 2 M aqueous sodium hydroxide solution, and extracted at least once, preferably repeatedly with diethyl ether. If desired, the resulting organic phases containing the reaction product can be dried over potassium carbonate, magnesium sulfate or sodium sulfate and the organic solvent can be removed under reduced pressure.

3. Furthermore, the reaction product can be isolated by removing the organic solvent under reduced pressure and separating the remaining residue by column chromatography to isolate the reaction product.

In the general description of the above process, the Grignard reagent may be replaced with the corresponding lithium compound. Corresponding lithium compounds, such as Grignard reagents, can be prepared by methods generally known to those skilled in the art, which can be reacted according to the invention in a manner similar to that disclosed above.

The compounds of formula (I) prepared according to the invention can be used, for example, as intermediates in the preparation of sulfur- or selenium-containing amines for chiral catalysis of diethyl zinc synthesis (Werth, Thomas; Tetrahydron Lett. 36; 1995, 7849-7852, Werth, Thomas et al., Helv. Chim. Acta 79, 1996, 1957-1966).

To illustrate and better understand the present invention, the following examples are provided. However, because of the general relevance of the principles disclosed above of the present invention, these examples are not intended to reduce the scope of the present invention only to these examples.

OrganoTitanium-triisopropoxide-induced symmetrical and asymmetrical dialkylation of carboxamides with Grignard reagent

According to the reaction shown in Scheme 1, the following reactions were carried out:

Scheme 1

In this table, iPr is iso-propyl, Me is methyl, Ph is phenyl and RF is "refluxing".

Claims (10)

A process for preparing a compound of formula (I), characterized by reacting a compound of formula (II) with a reagent of formula (III) and an organotitanate of formula (IV) in a suitable solvent: Formula I Formula II Formula III ZR ⁴ Formula IV R ⁵ Tix _3-n (OR) _n Where R ¹ , R ² and R ³ are independently of each other H, A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , or -NR ⁸ R ^9, or Or one or more additional heteroatoms selected from the group consisting of -S-, -O- and -NR ^6- , in addition to nitrogen, in which R ¹ and R ² , or R ¹ and R ³ , or R ⁸ and R ⁹ are bonded together; Can optionally form a cyclic ring having 3 to 8 carbon atoms, R ⁴ and R ⁵ are the same or different and are A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , or -NR ⁸ R ⁹ , wherein R ⁸ And R ⁹ is as defined above, or R ⁸ and R ⁹ are bonded to each other to optionally add one or more heteroatoms selected from the group consisting of —S—, —O— and —NR ⁶ — in addition to one nitrogen atom; To form a cyclic ring having 3 to 8 carbon atoms, provided that the R ⁴ and R ⁵ radicals in the β-position each have one or less hydrogen atoms, R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently of each other A or Ar, wherein A is a straight or branched alkyl radical having 1 to 10 carbon atoms; Straight or branched alkenyl radicals having 2 to 10 carbon atoms; Straight or branched alkynyl radicals having 2 to 10 carbon atoms; Substituted or unsubstituted cycloalkyl radical having 3 to 8 carbon atoms; Or a monounsaturated or polyunsaturated cycloalkyl radical having 3 to 8 carbon atoms, Ar is a substituted or unsubstituted aryl radical having 6 to 20 carbon atoms, Z is Li or MgX, where X is Hal and Hal is Cl, Br or I, R is alkyl of 1 to 10 carbon atoms or aryl of 6 to 20 carbon atoms, n is an integer of 1-3. The method of claim 1, a) Carboxamide of formula (II) and organotitanate of formula (IV) are initially subjected to a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether at an atmosphere of inert gas at 10 to 30 ° C. In the b) dropwise adding a solution comprising the nucleophilic reagent of formula III, c) reacting the mixture under agitation and post-treatment in a conventional manner after the reaction has ended. The method according to claim 1 or 2, a) the process is carried out at 15 to 20 ° C. The method according to claim 1 or 2, a) the process is carried out at room temperature. The method according to any one of claims 1 to 4, The nucleophilic reagent used is a lithium compound of formula III wherein R ⁴ is as defined in claim 1. The method according to any one of claims 1 to 5, The nucleophilic reagent used is a compound of formula III wherein R ⁴ is methyl, cyclopropyl, phenyl or p-fluorophenyl. The method according to any one of claims 1 to 6, An organotitanate of the formula IV, wherein R ⁵ is methyl, cyclopropyl, phenyl or p-fluorophenyl is used. The method according to any one of claims 1 to 7, The compound to be reacted is represented by formula II wherein R ¹ , R ² and R ³ are independently of each other H, methyl, ethyl, n- or isopropyl, iso-, secondary- or tert-butyl, n-hexyl, Phenyl or benzyl). The method according to any one of claims 1 to 8, The amount of the compound of the formula III and the compound of the formula IV is preferably the same, each 0.7 to 1.3 equivalents, preferably 0.9 to 1.1 equivalents based on the amount of the compound of formula II. The method according to any one of claims 1 to 9, The solvent used is an aliphatic or aromatic hydrocarbon or an ether, preferably toluene, n-hexane, cyclohexane, benzene or diethyl ether.