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

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.

1 . Process for preparing compounds of the general formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1 , R 2  and R 3  independently of one another are H, A, Ar, —Si(R 6 ) 3 , —Sn(R 6 ) 3 , —SR 7 , —OR 7 , —NR 8 R 9  or R 1  and R 2  or R 1  and R 3  or R 8  and R 9  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 —NR 6 —,  
 R 4  and R 5  are A, Ar, —Si(R 6 ) 3 , —Sn(R 6 ) 3 , —SR 7 , —OR 7 , —NR 8 R 9 , in which R 8  and R 9  are as defined above or R 8  and R 9  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 —NR 6 —;  
  or where two radicals R 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 —NR 6 —,  
  with the proviso that R 4  and R 5  in the β position may have at most one hydrogen atom in each case,  
 R 6 , R 7 , R 8  and R 9  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)  
                     
  in which R 1 , R 2  and R 3  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-R 4   (IIIA) Z-R 5   (IIIb)  
 in which  
 R 4  and R 5  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 . 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 . Process according to  claim 1  or  2 , characterized in that it is carried out in the presence of a cocatalyst.  
     
     
         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 . 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) R 3 SiX  (VI)  
       or of the general formula (VII)  
       R o -(X) m —Si—Y—(Si) p -(X) q -R o   (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#(CH 2 ) n  if m=0.  
 
     
     
         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)  
       MX 4-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 . 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    R 4  and R 5  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 . Process according to  claim 7 , characterized in that process step a) is carried out at a Temperature of from 15 to 25° C.  
     
     
         9 . Process according to  claim 7 , characterized in that the process step a) is carried out at room temperature.  
     
     
         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 R 4  and R 5  can have the meanings given in  claim 1  or  claim 7 .  
     
     
         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 R 4  and R 5  are methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, cyclopentyl, cyclohexyl, allyl, vinyl, phenyl or benzyl.  
     
     
         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 R 1 , R 2  and R 3  independently of one another are H, methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, phenyl or benzyl.  
     
     
         13 . Catalyst system, comprising a metal alkoxide of the general formula (IV)  
       MX 4-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  
 and a cocatalyst of the general formula (V), (VI)  
 M′ (s+) (O-isopropyl) s   (V)  
 R 3 SiX  (VI)  
 or of the general formula (VII)  
 R o -(X) m —Si—Y—(Si) p -(X) q —R o   (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≠(CH 2 ) n  if m=0.  
 
     
     
         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      (CH 3 ) 3 SiCl    (CH 3 ) 2 ClSi(CH 2 ) 2 SiCl(CH 3 ) 2      (CH 3 ) 2 ClSi(CH 2 ) 3 CN    [(CH 3 ) 3 Si] 2 O    [(CH 3 ) 3 Si] 2 NH and    [(CH 3 ) 3 Si] 2 .    
     
     
         15 . Catalyst system according to  claim 13 , comprising, as metal alkoxide, titanium tetraisopropoxide.  
     
     
         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 .