Process for the catalytic asymmetric disubstitution of carboxamides using 2 different Grignard reagents
OwnerHerwig Buchholz, Urs Welz-Biermanninventors
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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.
Claims16
Process for preparing compounds of the general formula (I)
- 12
- 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)
- 13
- 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.
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.
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.
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.
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.
Dependencies are inferred from the claim text.