U.S. patent application number 10/322570 was filed with the patent office on 2003-07-03 for process for the catalytic asymmetric disubstitution of carboxamides using 2 different grignard reagents.
Invention is credited to Buchholz, Herwig, Welz-Biermann, Urs.
Application Number | 20030125549 10/322570 |
Document ID | / |
Family ID | 7871277 |
Filed Date | 2003-07-03 |
United States Patent
Application |
20030125549 |
Kind Code |
A1 |
Buchholz, Herwig ; et
al. |
July 3, 2003 |
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.
Inventors: |
Buchholz, Herwig;
(Frankfurt, DE) ; Welz-Biermann, Urs; (Mannheim,
DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
7871277 |
Appl. No.: |
10/322570 |
Filed: |
December 19, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10322570 |
Dec 19, 2002 |
|
|
|
09719823 |
Feb 23, 2001 |
|
|
|
6512145 |
|
|
|
|
09719823 |
Feb 23, 2001 |
|
|
|
PCT/EP99/04250 |
Jun 18, 1999 |
|
|
|
Current U.S.
Class: |
544/59 ; 544/106;
544/358; 548/146; 548/215; 548/300.1; 556/128; 556/410;
564/415 |
Current CPC
Class: |
C07C 209/66 20130101;
C07D 295/023 20130101; C07C 209/66 20130101; C07C 211/27
20130101 |
Class at
Publication: |
544/59 ; 544/106;
544/358; 548/146; 548/215; 548/300.1; 556/128; 556/410;
564/415 |
International
Class: |
C07D 279/12; C07D
265/30; C07F 003/06; C07D 277/04; C07D 277/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 1998 |
DE |
198 27 163.8 |
Claims
1. Process for preparing compounds of the general formula (I) 12in
which R.sup.1, R.sup.2 and R.sup.3 independently of one another are
H, A, Ar, --Si(R.sup.6).sub.3, --Sn(R.sup.6).sub.3, --SR.sup.7,
--OR.sup.7, --NR.sup.8R.sup.9 or R.sup.1 and R.sup.2 or R.sup.1 and
R.sup.3 or R.sup.8 and R.sup.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.sup.6--, R.sup.4 and R.sup.5 are A, Ar, --Si(R.sup.6).sub.3,
--Sn(R.sup.6).sub.3, --SR.sup.7, --OR.sup.7, --NR.sup.8R.sup.9, in
which R.sup.8 and R.sup.9 are as defined above or R.sup.8 and
R.sup.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.sup.6--; or where two radicals
R.sup.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.sup.6--, with the proviso that
R.sup.4 and R.sup.5 in the .beta. position may have at most one
hydrogen atom in each case, R.sup.6, R.sup.7, R.sup.8 and R.sup.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) 13 in which R.sup.1, R.sup.2 and R.sup.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.sup.4 (IIIA) Z-R.sup.5 (IIIb) in
which R.sup.4 and R.sup.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'.sup.(s+)(O-isopropyl).su- b.s (V) R.sub.3SiX (VI) or of the
general formula (VII)
R.sub.o-(X).sub.m--Si--Y--(Si).sub.p-(X).sub.q-R.sub.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.sub.2).sub.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.sub.4-n(OR).sub.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.degree. 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.sup.4 and R.sup.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.degree. 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.sup.4 and R.sup.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.sup.4 and
R.sup.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.sup.1, R.sup.2 and R.sup.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.sub.4-n(OR.sub.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'.sup.(s+)(O-isopropyl).sub.s (V)
R.sup.3SiX (VI) or of the general formula (VII)
R.sub.o-(X).sub.m--Si--Y--(Si).sub.p-(X).sub.q--R.sub.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.noteq.(CH.sub.2).sub.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).sub.2 Al(OiPr).sub.3 (CH.sub.3).sub.3SiCl
(CH.sub.3).sub.2ClSi(CH.sub.2).sub.2S- iCl(CH.sub.3).sub.2
(CH.sub.3).sub.2ClSi(CH.sub.2).sub.3CN [(CH.sub.3).sub.3Si].sub.2O
[(CH.sub.3).sub.3Si].sub.2NH and [(CH.sub.3).sub.3Si].sub.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.
Description
[0001] 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.
[0002] 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.
[0003] 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.
[0004] Using the process according to the invention, it is possible
to prepare asymmetrically substituted amino compounds with a
considerably improved yield.
[0005] Accordingly, the present invention provides a process for
preparing compounds of the general formula (I) 1
[0006] in which
[0007] R.sup.1, R.sup.2 and R.sup.3 independently of one another
are H, A, Ar, --Si(R.sup.6).sub.3, --Sn(R.sup.6).sub.3, --SR.sup.7,
--OR.sup.7, --NR.sup.8R.sup.9 or R.sup.1 and R.sup.2 or R.sup.1 and
R.sup.3 or R.sup.8 and R.sup.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.sup.6--,
[0008] R.sup.4 and R.sup.5 are A, Ar, --Si(R.sup.6).sub.3,
--Sn(R.sup.6).sub.3, --SR.sup.7, OR.sup.7, --NR.sup.8R.sup.9, in
which R.sup.8 and R.sup.9 are as defined above or R.sup.8 and
R.sup.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.sup.6--;
[0009] or where two radicals R.sup.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.sup.6,
[0010] with the proviso that R.sup.4 and R.sup.5 in the .beta.
position may have at most one hydrogen atom in each case,
[0011] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one
another are A or Ar,
[0012] 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
[0013] Ar is a substituted or unsubstituted aryl radical having
6-20 C atoms,
[0014] characterized in that a compound of the general formula (II)
2
[0015] in which R.sup.1, R.sup.1 and R.sup.3 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-R.sup.4 (IIIa)
Z-R.sup.5 (IIIb)
[0016] in which
[0017] R.sup.4 and R.sup.5 have the meaning given for the formula
(I) and
[0018] Z is Li or MgX where
[0019] X is Hal and
[0020] Hal is Cl, Br or I.
[0021] According to the invention, the process is carried out in
the presence of catalytic amounts of a metal alkoxide of the
general formula (VI):
MX.sub.4-n(OR).sub.n (IV)
[0022] in which
[0023] M is titanium, zirconium or hafnium,
[0024] X is Cl, Br, I and
[0025] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C
atoms
[0026] n an integer from 1 to 4.
[0027] Preference is given to using metal alkoxides in which R is
isopropyl. Particular preference is given to using the metal
alkoxide Ti(OiPr).sub.4 in which iPr is an isopropyl radical.
[0028] 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)
M'.sup.(s+)(O-isopropyl).sub.s (V)
R.sub.3SiX (VI)
[0029] or of the general formula (VII)
R.sub.o-(X).sub.m--Si--Y--(Si).sub.p-(X).sub.q--R.sub.o (VII)
[0030] in which
[0031] M' is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
[0032] s is an integer from 1 to 4 and is the oxidation stage of
the metal,
[0033] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C
atoms,
[0034] X is F, Cl, Br, CN,
[0035] m is 0, 1,
[0036] n is 1 to 10,
[0037] o is 0, 2, 3,
[0038] p is 0, 1 and
[0039] q is 0, 1,
[0040] with the proviso that o=3 and Y.noteq.(CH.sub.2).sub.n if
m=0.
[0041] Thus, the invention also provides a process, which is
characterized in that
[0042] 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,
[0043] b) a solution comprising a nucleophilic reagent of the
general formula (IIIa) or (IIIb) is added dropwise and
[0044] c) the mixture is allowed to react with stirring and, after
the reaction has ended, worked up in a customary manner.
[0045] 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).
[0046] 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.sup.1, R.sup.2 and R.sup.3
independently of one another can have the following meanings:
[0047] H or
[0048] 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
[0049] 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.sub.2, F, Cl, Br, NH.sub.2, NHA,
NA.sub.2, OH and OA, where A can have the meanings given above, can
be mono-, poly-, or fully halogenated, preferably fluorinated,
or
[0050] aralkenyl or aralkynyl, where the aryl, alkenyl and alkynyl
groups can in each case have the given meanings, sucn as, for
example, in phenylethynyl.
[0051] Good yields are in particular also obtained using
carboxamides in which R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3
together form a cyclic ring having 3-8 C atoms which, in addition
to nitrogen, contains further heteroatoms, such as --S--, --O-- or
--NR.sup.6--. Particular preference is given here to compounds in
which R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3 form a simple
cyclic ring which includes the nitrogen of the carboxamide or in
which R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3 form a cyclic ring
which contains, as further heteroatom, an oxygen atom.
[0052] Thus, high yields are obtained in this manner when the
starting materials used are compounds such as, for example, or
3
[0053] The nucleophilic reagent used can be Grignard reagents or
organolithium compounds of the general formulae (IIIa) and (IIIb),
in which the radicals
[0054] R.sup.4 and R.sup.5 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,
[0055] 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.sub.2, F,
Cl, Br, NH.sub.2, NHA, NA.sub.2, OH and OA, where A can have the
meanings given above, can be mono-, poly- or fully halogenated,
preferably fluorinated,
[0056] 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.sub.2, F, Cl, Br,
NH.sub.2, NHA, NA.sub.2, OH and OA, where A can have the meanings
given above, can be mono-, poly- or fully halogenated, preferably
fluorinated,
[0057] 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.
[0058] Furthermore, the radicals R.sup.4 and RS in the general
formulae (IIIa) and (IIIb) can be --Si(R.sup.6),
--Sn(R.sup.6).sub.3, --SR.sup.7, --OR.sup.7, --NR.sup.8R.sup.9, in
which R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one
another can have the abovementioned meanings or R.sup.3 and R.sup.9
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 --NR.sup.6--.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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)
M'.sup.(s+)(O-isopropyl).sub.s (V)
R.sub.3SiX (VI)
[0063] or of the general formula (VII)
R.sub.o-(X).sub.m--Si--Y--(Si).sub.p-(X).sub.q--R.sub.o (VII)
[0064] in which
[0065] M'is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
[0066] s is an integer from 1 to 4 and is the oxidation stage of
the metal,
[0067] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C
atoms,
[0068] X is F, Cl, Br, CN,
[0069] m is 0, 1,
[0070] n is 1 to 10,
[0071] o is 0, 2, 3,
[0072] p is 0, 1, and
[0073] q is 0, 1,
[0074] with the proviso that o=3 and Y.noteq.(CH.sub.2).sub.n if
m=0.
[0075] 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.
[0076] 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.
[0077] Particularly suitable cocatalysts are, inter alia, the
following silicon compounds:
[0078] (CH.sub.3).sub.3SiCl
[0079] (CH.sub.3).sub.2ClSi (CH.sub.2).sub.2SiCl
(CH.sub.3).sub.2
[0080] (CH.sub.3).sub.2ClSi (CH.sub.2).sub.3CN
[0081] [(CH.sub.3).sub.3Si].sub.2O
[0082] [(CH.sub.3).sub.3Si].sub.2NH and
[0083] [(CH.sub.3).sub.3Si].sub.2.
[0084] 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.
[0085] 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:
4
[0086] 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.
[0087] 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.degree. C., preferably 15-25.degree.
C., particularly preferably to a temperature of about 20.degree. 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.degree. 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.
[0088] 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.
[0089] 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.degree. C., preferably to from 60 to
70.degree. C., in particular to 65.degree. C.
[0090] 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.
[0091] 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).
[0092] For example, 5 mmol of starting material are, at 20.degree.
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.degree. 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.degree. C. Stirring is
continued for one hour, until the reaction has gone to
completion.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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:
[0097] 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).
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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).
[0102] 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.
EXAMPLES
[0103] Titanium-tetraisopropoxide-induced asymmetric dialkylation
of carboxamides using 2 different Grignard reagents
[0104] According to the reaction shown in Equation 1, the following
reactions were carried out using one equivalent of
(CH.sub.3).sub.3SiCl as cocatalyst:
1TABLE 1 Ti(OiPr).sub.4-induced reaction of carboxamides with
R.sup.4MgX and R.sup.5MgX. 5 R.sup.4MgX/ Reaction Amide Product
Yield R.sup.5MgX conditions 6 7 71% MeMgBr/ PhMgBr 1 h/25.degree.
C./ 3 mol % Ti(OiPr).sub.4/5 mmol cocat 8 9 81% PhMgBr/ BnMgCl 1
h/RT/ 3 mol % Ti(OiPr).sub.4 10 11 79% MeMgBr/ PhMgBr 3 mol %
Ti(OiPr).sub.4/5 mmol cocat Me = Methyl, Ph = Phenyl, iPr =
iso-Propyl, Bn = Benzyl, cocat = (CH.sub.3).sub.3SiCl
* * * * *