Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-02-23
2002-09-10
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C546S184000, C564S446000, C564S448000, C564S452000, C564S453000, C564S455000, C564S462000, C564S471000
Reexamination Certificate
active
06448445
ABSTRACT:
The present invention relates to processes for disubstituting carboxamides using at least one Grignard reagent in the presence of an organometallic compound as catalyst and a further organometallic compound as cocatalyst.
It is already known from the prior art that reactions of Grignard reagents with carbonyl compounds under catalytic action of tetraisopropyl orthotitanate results in cycloalkyl formation (O. G. Kulinovich, S. V. Sviridov, D. A. Vasilevskii, A. I. Savchenko, T. S. Pritytskaya, J. Org. Chem. USSR, 1991, 27, 250-253; O. G. Kulinovich, S. V. Sviridov, D. A. Vasilevskii, Synthesis, 1991, 234).
This course of the reaction with &bgr;-hydride elimination of the alkyl-substituted reagents is confirmed in the prior art below: (V. Chaplinski, Dissertation, Göttingen, 1996; V. Chaplinski, A. de Meijere, Angew. Chem. 1996, 108, 491; V. Chaplinski, H. Winsel, M. Kordes, A. de Meijere, Synlett, 1997, 111-114)
Accordingly, it was the object, in the reaction of carboxamides in the presence of organotitanium compounds, to suppress &bgr;-hydride elimination and thus cyclopropane formation, so that carboxamides can be converted, by disubstitution with Grignard reagents having two &bgr;-hydrogens among their substituents, into the corresponding substituted amino compounds.
According to the invention, this is achieved by using a catalyst system comprising an organometal compound as catalyst and a further organometal compound as cocatalyst.
Accordingly, the present invention provides 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
and R
5
, which may be identical or different, are A, Ar, —Si(R
6
)
3
, —Sn(R
6
)
3
, —SR
7
, —OR
7
, —NR
8
R
9
, —C(R
10
) (R
8
)CH
2
R
9
, in which R
8
, R
9
and R
10
or R
4
and R
5
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
—;
with the proviso that the radicals R
4
and R
5
in the &bgr; position in each case have at least two hydrogen atoms,
R
6
, R
7
, R
8
and R
9
independently of one another are A or Ar,
R
10
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
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
—,
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 in each case one nucleophilic reagent of the general formula (IIIa) and one 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.
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
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.
Preference is given to using metal alkoxides in which R is isopropyl. Particular preference is given to using the metal alkoxide Ti(OiPr)
4
in which iPr is an isopropyl radical.
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′
(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 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=0.
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 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,
b) a solution comprising a nucleophilic reagent of the general formulae (IIIa) and (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.
Experiments have shown that, using a nucleophilic reagent of the general formula (IIIa) or (IIIb), which may be Grignard reagents and which may be 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 symmetrically or unsymmetrically substituted compounds of the general formula (I).
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
1
, R
2
and R
3
independently of one another can have the following meanings:
H or
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
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
2
, F, Cl, Br, NH
2
, NHA, NA
2
, OH and OA, where A can have the meanings given above, can be mono-, poly-, or fully halogenated, preferably fluorinated, or
aralkenyl or aralkynyl, where the aryl, alkenyl and alkynyl groups can in each case have the given meanings, such as, for example, in phenylethynyl.
Good yields are in particular also obtained using carboxamides in which R
1
and R
2
or R
1
and R
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
6
—. Particular preference
Buchholz Herwig
Meijere Armin
Welz-biermann Urs
Kumar Shailendra
Merck Patent Gesellschaft mit beschraenkter Haftung
Millen White Zelano & Branigan P.C.
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