Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-03-07
2003-02-04
Chang, Ceila (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S373000, C564S391000, C556S012000, C556S095000
Reexamination Certificate
active
06515180
ABSTRACT:
The present invention relates to a process for disubstituting carboxamides using Grignard reagents in the presence of organometallic compounds as catalyst and a further organometallic compound as cocatalyst.
It is already known from the prior art, in particular from Collect. Czech. Chem. Commun. 1939, 11, 506 and 1959, 24, 110, that the symmetric dialkylation of carboxamides with a Grignard reagent can give amines, the yields of which, however, are not satisfactory.
Accordingly, it was the object of the invention to prepare symmetrically substituted amino compounds with a considerably improved yield by reacting carboxamides with a Grignard reagent.
Using the process according to the invention, it is possible to prepare symmetrically substituted amino compounds with considerably improved yields.
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
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
—; or where two radicals R
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
6
, with the proviso that R
4
in the &bgr; position has at most one hydrogen atom,
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, 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 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.
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.
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
0
—(X)
m
—Si—Y—(Si)
p
—(X)
q
—R
0
(VII)
in which
M′ is Al, Ca, Na, R, 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
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 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 alkoxide selected from the group consisting of titanium alkoxide, zirconium alkoxide and hafnium alkoxide 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 the general formula (IIIa′) or (IIIb′)
X—R
4
(IIIa′)
or
X—R
4
—R
4
—X (IIIb′)
in which R
4
and X have the meanings given above, is added dropwise
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 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 alkoxide, zirconium alkoxide or hafnium alkoxide in a simple manner into symmetrically 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 is given here to compounds i
Buchholz Herwig
Meijere Armin
Welz-Biermann Urs
Chang Ceila
Merck Patent Gesellschaft
Wright Sonya
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