Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-23
2002-11-12
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S215000, C564S391000, C564S414000, C564S455000
Reexamination Certificate
active
06479661
ABSTRACT:
The present invention relates to a process for disubstituting carboxamides using a Grignard reagent in the presence of organotitanium compounds.
It is already known from the prior art, in particular 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.
It is also 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 and asymmetrically substituted amino compounds with a considerably improved yield by reacting carboxamides with Grignard reagents.
Using the process according to the invention, it is possible to prepare symmetrically or asymmetrically 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
and R
5
are identical or different and are 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
—; with the proviso that R
4
and R
5
in the &bgr; position have 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 unsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radial having 6-20 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 (III)
Z—R
4
(III)
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 an organotitanate of the general formula (IV):
R
5
Tix
3—n
(OR)
n
(IV)
in which
R
5
has the meaning given for the formula (I), and
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 3.
Preference is given to using organotitanates in which R is isopropyl. Particular preference is given to using ethyl-, phenyl-, cyclopropyl- or p-fluorophenyl-triisopropyltitanate.
Thus, the invention also provides a process, which is characterized in that
a) a carboxamide of the general formula (II) and an organotitanate 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 (III) 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 (III), which may be a Grignard reagent and which is added as such to the reaction mixture, it is possible to convert carboxamides of the general formula (II) in the presence of organotitanates in a simple manner into symmetrically or asymmetrically 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 cyclopropyli 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 a 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 in which R
1
and R
2
or R
1
and R
3
form a simple cyclic ring which includes the nitrogen of the carboxamide or in which R
1
and R
2
or R
1
and R
3
form a cyclic ring which contains, as further heteroatom, an oxygen atom. Thus, high yields are obtained in this manner when the starting materials used are compounds such as, for example,
The nucleophilic reagent used can be a Grignard reagent or an organolithium compound of the general formula (III) in combination with organotitanates of the general formula (IV), in which the radicals
R
4
and R
5
are preferably an alkyl radical having 1 to 10 C atoms, such as methyl, isopropyl, iso- or tert-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, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl,
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 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
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
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 h
Buchholz Herwig
Chaplinski Vladimir
Meijere Armin
Welz-Biermann Urs
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