U.S. patent application number 10/162257 was filed with the patent office on 2003-01-09 for catalytic titanium (iv) oxide, mediated geminal symmetric dialkylation of carboxamides.
This patent application is currently assigned to Merck Patent GmbH. Invention is credited to Buchholz, Herwig, Welz-Biermann, Urs.
Application Number | 20030009029 10/162257 |
Document ID | / |
Family ID | 7871278 |
Filed Date | 2003-01-09 |
United States Patent
Application |
20030009029 |
Kind Code |
A1 |
Buchholz, Herwig ; et
al. |
January 9, 2003 |
Catalytic titanium (IV) oxide, mediated geminal symmetric
dialkylation of carboxamides
Abstract
The present invention relates to a process preparing compounds
of the general formula (I) 1 wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined herein.
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
|
Assignee: |
Merck Patent GmbH
Frankfurt Strasse 250
Darmstadt
DE
64293
|
Family ID: |
7871278 |
Appl. No.: |
10/162257 |
Filed: |
June 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10162257 |
Jun 5, 2002 |
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09719810 |
Apr 20, 2001 |
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6420302 |
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Current U.S.
Class: |
544/56 ; 544/106;
544/162; 544/174; 544/178; 544/229; 544/359; 544/398; 544/402;
546/14; 546/229; 546/232 |
Current CPC
Class: |
C07C 209/68 20130101;
B01J 2231/341 20130101; B01J 21/063 20130101; B01J 2231/40
20130101; B01J 31/0231 20130101; B01J 31/0212 20130101; C07D 295/03
20130101; B01J 31/0275 20130101; B01J 21/06 20130101; B01J 31/0274
20130101; C07C 209/68 20130101; C07C 211/16 20130101; C07C 209/68
20130101; C07C 211/27 20130101 |
Class at
Publication: |
544/56 ; 544/106;
544/174; 544/162; 544/178; 544/359; 544/398; 544/402; 544/229;
546/14; 546/229; 546/232 |
International
Class: |
C07F 007/02; C07D
279/10; C07D 279/12; C07D 265/30 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 1998 |
DE |
19827164.6 |
Claims
1. A process for preparing compounds of the general formula (I)
25in 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 is 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 or two radicals R.sup.4 can be attached to one another and
together form a cyclic ring having 3 C atoms, 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) 26in 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) or a
nucleophilic reagent of the general formula (IIIb)Z-R.sup.4
(IIIa)Z-R.sup.4--R.sup.4-Z (IIIb)in which R.sup.4 has the meaning
given for the formula (I), and Z is Li or MgX where X is Hal and
Hal is Cl, Br or I, which is/are generated in situ or added
directly, and the process is carried out in the presence of
catalytic amounts of a metal dioxide selected from the group
consisting of titanium dioxide, zirconium dioxide and hafnium
dioxide.
2. A process according to claim 1, characterized in that it is
carried out in the presence of a cocatalyst.
3. A process according to claim 1, characterized in that it is
carried out in the presence of a metal isopropoxide or an
alkylsilyl halide cocatalyst.
4. A process according to claim 2, characterized in that the
cocatalyst used is a metal isopropoxide of the general formula (IV)
or an alkylsilyl halide of the general formula (V)M'.sup.(s+)
(O-isopropyl).sub.s (IV)R.sub.3SiX (V)in which M' is Al, Ca, Na, K,
Si or Mg, s is an integer from 1 to 4 and is the oxidation state 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, or CN.
5. A process according to claim 1, characterized in that the
catalyst used is titanium dioxide.
6. A process according to claim 1, characterized in that a) a
carboxamide of the general formula (II), 1-15 mol %, based on the
carboxamide, of a metal dioxide selected from the group consisting
of titanium dioxide, zirconium dioxide and hafnium dioxide 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 a nucleophilic reagent of the
general formula (IIIa) or (IIIb) in which R.sup.4 is 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 or two radicals R.sup.4 can be attached to
one another and together form a cyclic ring having 3 C atoms,
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, Z is
Li or MgX where X is Hal and Hal is Cl, Br or I, 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, or in that, if
Z=MgX, a') magnesium turnings, a carboxamide of the general formula
(II), 1-15 mol %, based on the carboxamide, of a metal dioxide
selected from the group consisting of titanium dioxide, zirconium
dioxide and hafnium dioxide 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') an alkyl halide,
dissolved in a solvent selected from the group consisting of
toluene, THF, n-hexane, benzene and diethyl ether, and of the
general formula (IIIa') of (IIIb')X--R.sup.4
(IIIa')orX--R.sup.4--R.sup.4--X (IIIb')in which R.sup.4 is 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 or two radicals R.sup.4 can be attached to
one another and together form a cyclic ring having 3 C atoms,
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, X is
Cl, Br, or I; is added dropwise, c') the mixture is allowed to
react with stirring and, after the reaction had ended, worked up in
a customary manner.
7. A process according to claim 6, characterized in that the
process step a) or a') is carried out at a temperature of
15-25.degree. C.
8. A process according to claim 6, characterized in that the
process step a) or a') is carried out at room temperature.
9. A process according to claim 1, characterized in that the
nucleophilic reagent used is a lithium compound of the general
formula (IIIa) or (IIIb) in which R.sup.4 is 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 or two radicals R.sup.4 can be attached to
one another and together form a cyclic ring having 3 C atoms,
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.
10. A process according claim 1, characterized in that the compound
that the nucleophilic reagent used is a compound of the general
formula (IIIa) or (IIIb) in which R.sup.4 is methyl, ethyl, n- or
isopropyl, iso-, sec- or tert-butyl, n-hexyl, cyclopentyl,
cyclohexyl, allyl, vinyl, phenyl or benzyl.
11. A process according to claim 1, 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.
12. A process for preparing compounds of the general formula (I)
27in 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 is 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 or two radicals R.sup.4 can be attached to one another and
together form a cyclic ring having 3 C atoms 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, by carrying out the process in the
presence of a catalyst system, comprising a metal dioxide selected
from the group consisting of titanium dioxide, and hafnium dioxide
and a cocatalyst of the general formula (IV), (V)M'.sup.(s+)
(O-isopropyl).sub.s (IV)R.sub.3SiX (V)in which M' is Al, Ca, Na, K,
Si or Mg, s is an integer from 1 to 4 and is the oxidation state 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, or CN, or the general formulae
(CH.sub.3).sub.2ClSi(CH.sub.2).sub.2SiCl(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 or [(CH.sub.3).sub.3Si].sub.2.
13. A process according to claim 4, wherein M.sup.1 is Mg or
Na.
14. A process according to claim 12, wherein M.sup.1 is Mg or Na.
Description
[0001] The present invention relates to a process for the symmetric
disubstitution of carboxamides at the geminal carbonyl C atom using
Grignard reagents in the presence of titanium dioxide, and to the
compounds, prepared by this process, of the general formula (I)
2
[0002] in which
[0003] 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--,
[0004] R.sup.4 is 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 or two radicals
R.sup.4 can be attached to one another and together form a cyclic
ring having 3 to 8 C atoms which can optionally contain, in
addition to one nitrogen atom, at least one heteroatom selected
from the group consisting of --S--, --O-- and --NR.sup.6--,
[0005] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one
another are A or Ar,
[0006] 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
[0007] Ar is a substituted or unsubstituted aryl radical having
6-20 C atoms.
[0008] In addition to monoalkylation, geminal dialkylations using
various titanium reagents have been included in studies on
titanium-mediated alkylation of carbonyl functions. The geminal
dimethyl structure, which is frequently found as a component in
terpenes and steroids, is particularly interesting here. It has
been found that a large number of ketones can be methylated with
the aid of (CH.sub.3).sub.2TiCl.sub.2 (M. T. Reetz, J. Westermann,
R. Steinbach, J. Chem. Soc., Chem. Commun. (1981) 237; M. T. Reetz,
J. Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050). However,
hitherto, no studies on the transfer of other alkyl building blocks
with the aid of various titanium reagents are known.
[0009] Geminal symmetric dialkylations of amides have been known
for a long time, on account of their reactions with Grignard
reagents (F. Kuffner, S. Sattler-Dornbach, W. Seifried, Mh. Chem.
(1962) 93, 469).
[0010] Hitherto, geminal dimethylations giving high yields have
only been reported for pure ketones or aldehydes, the reactions
being titanium-mediated alkylations. To this end, the reagents
ZnMe.sub.2 or AlMe.sub.3 are required for synthesising the required
organotitanium compound TiMe.sub.2Cl.sub.2, since ethereal
solutions of MeMgCl/TiCl.sub.4 only result in a simple addition of
the methyl group to keto groups (M. T. Reetz, J. Westermann, R.
Steinbach, J. Chem. Soc., Chem. Commun. (1981) 237; M. T. Reetz, J.
Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050).
[0011] In the hitherto known symmetric dialkylations of amides
which are carried out with the aid of a Grignard reagent, the
products are in most cases only obtained as byproducts. The yields
that are obtained are in the range of a few percent, up to at most
about 50%.
1TABLE 1 Amide Grignard Yield Lit. 3 4 11% M. Busch, M.
Fleischmann, Chem. Ber. (1910), 43, 2553 5 6 53% R. Lukes, J.
Langthaler, Collect Czech. Chem. Commun. (1959), 24, 110 7 8 30% R.
Lukes, J. Langthaler, Collect Czech. Chem. Commun. (1959), 24, 110
9 10 41% R. Lukes, K. Smolek, Collect Czech. Chem. Commun. (1939),
11, 506
[0012] Accordingly, it is the object of the present invention to
provide an inexpensive process which is easy to carry out and
gives, from amides of the general formula (II) 11
[0013] in which R.sup.1, R.sup.2 and R.sup.3 have the meanings
given above, compounds of the general formula (I) given above which
are substituted symmetrically at the geminal carbonyl C atom, in
high yield.
[0014] This object is achieved by a process for preparing compounds
of the general formula (I) 12
[0015] in which
[0016] 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--,
[0017] R.sup.4 is 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 or two radicals
R.sup.4 can be attached to one another and together form a cyclic
ring having 3 to 8 C atoms which can optionally contain, in
addition to one nitrogen atom, at least one heteroatom selected
from the group consisting of --S--, --O-- and --NR.sup.6--,
[0018] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one
another are A or Ar,
[0019] 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
[0020] Ar is a substituted or unsubstituted aryl radical having
6-20 C atoms,
[0021] from compounds of the formula (II) 13
[0022] in which R.sup.1, R.sup.2 and R.sup.3 have the meanings
given above for formula (I), by reaction with a nucleophilic
reagent of the general formula (IIIa) or a nucleophilic reagent of
the general formula (IIIb)
Z-R.sup.4 (IIIa)
Z-R.sup.4-R.sup.4-Z (IIIb)
[0023] in which
[0024] R.sup.4 has the meaning given for the formula (I), and
[0025] Z is Li or MgX where
[0026] X is Hal and
[0027] Hal is Cl, Br or I,
[0028] where the latter is generated in situ or added directly.
[0029] According to the invention, the process is carried out in
the presence of catalytic amounts of a metal oxide selected from
the group consisting of titanium dioxide, zirconium dioxide and
hafnium dioxide.
[0030] 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 (IV) and alkylsilyl
halides of the general formula (V)
M'.sup.(s+)(O-isopropyl).sub.s (IV)
R.sub.3SiX (V)
[0031] or of the general formula (VI)
R.sub.0--(X).sub.m--Si--Y--(Si).sub.p--(X).sub.q--R.sub.0 (VI)
[0032] in which
[0033] M' is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
[0034] s is an integer from 1 to 4 and is the oxidation state of
the metal,
[0035] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C
atoms,
[0036] X is F, Cl, Br, CN,
[0037] m is 0, 1,
[0038] n is 1 to 10,
[0039] o is 0, 2, 3,
[0040] p is 0, 1 and
[0041] q is 0, 1,
[0042] with the proviso that o=3 and Y.noteq.(CH.sub.2).sub.n if
m=0.
[0043] Thus, the invention also provides a process, which is
characterized in that
[0044] a) a carboxamide of the general formula (II), 1-15 mol %,
based on the carboxamide, of a metal dioxide selected from the
group consisting of titanium dioxide, zirconium dioxide and hafnium
dioxide 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,
[0045] b) a solution comprising a nucleophilic reagent of the
general formula (IIIa) or (IIIb) is added dropwise and
[0046] c) the mixture is allowed to react with stirring and, after
the reaction has ended, worked up in a customary manner,
[0047] or in that, if Z=MgX,
[0048] a') magnesium turnings, a carboxamide of the general formula
(II), 1-15 mol %, based on the carboxamide, of a metal oxide
selected from the group consisting of titanium dioxide, zirconium
dioxide and hafnium dioxide 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,
[0049] b') an alkyl halide, dissolved in a solvent selected from
the group consisting of toluene, THF, n-hexane, benzene and diethyl
ether, and of the general formula (IIIa') or (IIIb')
X--R.sup.4 (IIIa')
or
X--R.sup.4--R.sup.4--X (IIIb')
[0050] in which R.sup.4 and X have the meanings given for the
formula (I), is added dropwise,
[0051] c') the mixture is allowed to react with stirring and, after
the reaction has ended, worked up in a customary manner.
[0052] Experiments have shown that, using a nucleophilic reagent of
the general formula (IIIa) or (IIIb), which may be a Grignard
reagent and which may either be generated in situ or 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 dioxide, zirconium dioxide or hafnium dioxide in a simple
manner into symmetrically substituted compounds of the general
formula (I).
[0053] 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:
[0054] H or
[0055] 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
[0056] 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
[0057] aralkenyl or aralkynyl, where the aryl, alkenyl and alkynyl
groups can in each case have the given meanings, such as, for
example, in phenylethynyl.
[0058] 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.
[0059] Thus, high yields are obtained in this manner when the
starting materials used are compounds such as, for example, 14
[0060] The nucleophilic reagent used can be a Grignard reagent or
an organolithium compound of the general formulae (IIIa) or (IIIb),
in which the radical
[0061] R.sup.4 is 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 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
[0062] is 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 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
[0063] is 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,
[0064] is 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.
[0065] Furthermore, the radicals R.sup.4 in the general formula
(IIIa) or (IIIb) can be --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.6,
R.sup.7, R.sup.8 and R.sup.9 independently of one another can have
the abovementioned meanings 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 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--; or
[0066] two radicals R.sup.4 in the general formula (IIIb) can be an
alkyl having 2-7 C atoms, so that, in the reaction according to the
invention, a compound of the general formula (I) is formed in which
two radicals R.sup.4 form a cyclic ring having 3 to 8 atoms.
[0067] Particularly preferably, R.sup.4 has the meaning of an alkyl
radical, such as, for example, methyl, ethyl, n- or isopropyl, n-,
sec- or t-butyl, pentyl, hexyl, or of a cycloalkyl radical, such
as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or of an aryl radical, such as, for example, phenyl, or of an
aralkyl radical, such as, for example, benzyl.
[0068] 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.
[0069] Particular preference according to the invention is given to
using Grignard compounds 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.
[0070] Furthermore, it was found that only if a cocatalyst is
added, the geminal symmetric 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.
[0071] Suitable cocatalysts for this reaction are metal
isopropoxides and alkylsilyl halides. Particularly suitable are
metal isopropoxides of the general formula (IV) and alkylsilyl
halides of the general formula (V)
M'.sup.(s+)(O-isopropyl).sub.s (IV)
R.sub.3SiX (V)
[0072] or of the general formula (VI)
R.sub.0--(X).sub.m--Si--Y--(Si).sub.p--(X).sub.q--R.sub.0 (VII)
[0073] in which
[0074] M' is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,
[0075] s is an integer from 1 to 4 and is the oxidation state of
the metal,
[0076] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C
atoms,
[0077] X is F, Cl, Br, CN,
[0078] m is 0, 1,
[0079] n is 1 to 10,
[0080] o is 0, 2, 3,
[0081] p is 0, 1 and
[0082] q is 0, 1,
[0083] with the proviso that o=3 and Y.noteq.(CH.sub.2).sub.n if
m=0.
[0084] Preference is given to using metal isopropoxides in which s
is an integer from 1 to 4 and is the oxidation state of the metal
and M' is Al, Ca, Na, K, Si or Mg. Particular preference is given
to Mg or Na.
[0085] 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.
[0086] Particularly suitable cocatalysts are, inter alia, the
following silicon compounds:
[0087] (CH.sub.3).sub.3SiCl
[0088] (CH.sub.3).sub.2ClSi(CH.sub.2).sub.2SiCl(CH.sub.3).sub.2
[0089] (CH.sub.3).sub.2ClSi(CH.sub.2).sub.3CN
[0090] [(CH.sub.3).sub.3Si].sub.2O
[0091] [(CH.sub.3).sub.3Si].sub.2NH and
[0092] [(CH.sub.3).sub.3Si].sub.2.
[0093] 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.
[0094] 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:
15
[0095] For carrying out the process according to the invention, the
catalyst used can be a commercial metal dioxide selected from the
group consisting of titanium dioxide, zirconium dioxide and hafnium
dioxide. Preference is given to using pulverulent titanium(IV)
dioxide. In the simplest case, this can be of technical grade. To
ensure simple removal after the reaction has ended, it is
advantageous to choose a quality which is not too fine. The metal
dioxide, preferably titanium dioxide, which is pre-dried by
heating, is employed as a suspension in a suitable pre-dried
solvent. 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.
[0096] A preferred embodiment of the process according to the
invention comprises initially charging the titanium dioxide 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 suspension 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 excess of the
nucleophilic reagent of the general formula (IIIa) or (IIIb), in
particular a Grignard reagent, is then slowly added to the
resulting reaction mixture that substitution of the geminal
carbonyl C atom by two identical substituents, i.e. a symmetric
substitution of the geminal carbonyl C atom, can take place. The
addition of a nucleophilic reagent 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 reagent, i.e. of the
Grignard reagent or the lithium compound, with efficient mixing,
preferably vigorous stirring. To shift the reaction equilibrium to
the side of the desired symmetrically substituted product, the
nucleophilic reagent used, preferably a Grignard reagent, is added
in an amount of from 2.1 to 3 mol per mole of starting material
that participates in the reaction. Preference is given to adding
the Grignard reagent in an amount of from 2.2 to 2.6 mol, based on
1 mol of starting material. If a nucleophilic reagent or Grignard
reagent of the general formula (IIIb) is used, only equimolar
amounts, based on the starting material, are added to the reaction
solution, corresponding to twice the number of reactive groups.
[0097] After the addition of the Grignard reagent has ended, the
reaction mixture is stirred for some time at a constant
temperature, until the reaction is brought to completion.
[0098] Another variant of the process according to the invention
comprises preparing the Grignard reagent in situ by reacting
magnesium with a compound of the general formula (IIIa') or (IIIb')
in which R.sup.4 and X have the meanings given above. In the in
situ preparation of the Grignard compounds, the amount of magnesium
is preferably 2 to 5 times the molar amount, preferably 2.8 to 3.2
times the molar amount, based on the compounds of the general
formula (II) used as starting material, and the amount of the
compound of the general formula (IIIa') or (IIIb') is 2 to 3.8
times the molar amount, preferably 2.2 to 2.6 times the molar
amount, based on the compound of the general formula (II).
[0099] Thus, by the synthesis according to the invention it is
possible to prepare symmetrically 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 (IV), (V) or
(VI), to reduce the reaction times considerably, in the most
favourable case to one hour, without this resulting in a reduction
in the yields obtained.
[0100] Thus, the present invention also provides the use of a
catalyst system comprising a metal dioxide selected from the group
consisting of titanium dioxide, zirconium dioxide and hafnium
dioxide as catalyst and a compound of the general formulae (IV),
(V) or (VI) with the meanings given above, and the use of this
catalyst system for preparing the symmetrically substituted
compounds of the general formula (I).
[0101] 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 suspension of 3 mol % of titanium (IV) oxide 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
12 mmol of Grignard reagent are then added at such a rate that the
temperature of the reaction mixture does not exceed 50.degree. C.
Stirring is continued for one hour, until the reaction has gone to
completion.
[0102] 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.
[0103] 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.
[0104] To remove the Lewis acid, it is possible, for example, to
add a suitable amount of saturated ammonium chloride 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.
[0105] 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:
[0106] 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).
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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).
[0111] 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
Titanium(IV)-oxide-induced Symmetric Dialkylation of Carboxamides
Using Grignard Reagents
[0112] 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:
2TABLE 2 TiO.sub.2-induced reaction of carboxamide with R.sub.4MgX
16 17 18 Reaction Amide Product Yield R.sup.4MgX conditions 19 20
95%.sup.[6] PhMgBr 1 h/RT/ 3 mol % TiO.sub.2 21 22 49%.sup.[6]
Cyclopen tyl-MgCl 1 h/RT/ 13 mol % TiO.sub.2 23 24 94%.sup.[6]
n-Hexyl-MgBr 1 h/RT/ 13 mol % TiO.sub.2 .sup.[6]Use of one
equivalent (CH.sub.3).sub.3SiCl as cocatalyst.
* * * * *