Catalyst system

Details Catalyst system Catalyst system

2001-04-20

2002-07-16

Bell, Mark L. (Department: 1755)

Catalyst, solid sorbent, or support therefor: product or process

Catalyst or precursor therefor

Organic compound containing

C502S171000, C502S242000, C502S349000, C502S350000

Reexamination Certificate

active

06420302

ABSTRACT:

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)
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
is 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
or two radicals R
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
6
—,
R
6
, R
7
, R 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.
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
3
)
2
TiCl
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.
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).
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
2
or AlMe
3
are required for synthesising the required organotitanium compound TiMe
2
Cl
2
, since ethereal solutions of MeMgCl/TiCl
4
only result in a simple addition of the methyl group to keto groups (M. T. Reetz, J. Westermann, R. Steinbach, J. Clem. Soc., Chem. Commun. (1981) 237; M. T. Reetz, J. Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050).
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%.
TABLE 1
Amide
Grignard
Yield
Lit.
11%
M. Busch, M. Fleischmann, Chem. Ber. (1910), 43, 2553

53%
R. Lukes, J. Langthaler, Collect. Czech. Chem. Commun. (1959), 24, 110

30%
R. Lukes, J. Langthaler, Collect. Czech. Chem. Commun. (1959), 24, 110

41%
R. Lukes, K. Smolek, Collect. Czech. Chem. Commun. (1939), 11, 506
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)
in which R
1
, R
2
and R
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.
This object is achieved by a 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
is 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
or two radicals R
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—, —C— and —NR
6
—,
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, from compounds of the formula (II)
in which R
1
, R
2
and R 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
4
  (IIIa)
Z—R
4
—R
4
—Z  (IIIb)
in which
R
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,
where the latter is generated in situ or added directly.
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.
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′
(s+)
(O-isopropyl)
s
  (IV)
R
3
SiX  (V)
or of the general formula (VI)
R
0
—(X)
m
Si—Y—(Si)
p
—(X)
q
R
0
  (VI)
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 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, 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=O.
Thus, the invention also provides a process, which is 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, 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,
b) a solution comprising a nucleophilic reagent of the general formula (IIIa) or (IIIb) 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 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,
b′) an alkyl halide, dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, and of

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