Preparation of substituted indoles

Details Preparation of substituted indoles Preparation of substituted indoles

2001-02-14

2002-05-07

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S495000

Reexamination Certificate

active

06384235

ABSTRACT:

The present invention relates to a process for preparing substituted indoles of the formula (I), in which substituted 2-alkynylanilines are cyclized in a polar aprotic solvent with the aid of a suitable alkali metal compound.
Simple, low-cost indole syntheses are of great general interest, since the indole structure is found in numerous natural products and in particular in pharmacologically active substances. To date, there are a number of principal routes leading to the desired indole derivatives.
Intramolecular addition of amino groups to a carbon-carbon triple bond with formation of indole derivatives is a reaction known from the literature. The reaction can be catalyzed, for example, by palladium complexes. This is described, inter alia, in the publication by K. Utimoto et al. in Tetrahedron Letters 29 (1992), 3915 ff.
Other publications disclose the use of molybdenum(0) compounds in these cyclization reactions. This can be found in the publications by F. E. McDonald et al. in Tetrahedron Letters 38 (1997), 7687 ff. and in Chem. Eur. J. 5 (1999), 3103 ff.
In a variant described in a plurality of publications by S. Cacchi et al., for example in Tetrahedron Letters 33 (1992), 3915 ff., Synlett 1997, 1393 ff., Tetrahedron Letters 50 (1994), 437 ff., it is possible to use, instead of the alkynylanilines, the corresponding trifluoroacetamides, the catalysts used here again being palladium complexes.
The synthesis of substituted indoles is furthermore described by Yamanaka et al. in Heterocycles 24 (1986), 31/32. Here, alkynylcarbanilates are cyclized in the presence of Na ethoxylate, and the N-bonded C(O)O-alkyl unit is removed by hydrolysis. This cyclization reaction does not work if the starting material used is a 2-alkynylaniline.
However, in all of these reactions it is frequently necessary to heat the reaction mixture to relatively high temperatures, and frequently, long reaction times are additionally required to achieve acceptable yields. These harsh reaction conditions, which are generally required, strongly restrict, inter alia, the range of the various functionalities which can be present in the 2-alkynylanilines.
It is an object of the present invention to provide a process which allows a simple preparation of the substituted indoles, with good yields and using short reaction times and low reaction temperatures. The process should furthermore permit the synthesis of substituted indoles having a large number of different substituents.
We have found that this object is achieved by a process for preparing compounds of the indole type of the formula
in which A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and
R
1
, R
2
independently of one another are H, a saturated, linear or branched aliphatic C
1
-C
20
-hydrocarbon radical, an unsaturated, linear or branched aliphatic C
2
-C
20
-hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C
3
-C
20
-hydrocarbon radical or an aromatic C
5
-C
20
-hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted, by cyclization of alkynylaminoaromatics of the formula
in which R
1
and R
2
are as defined in formula (I) and R
1
, R
2
or A may be attached to an organic or inorganic carrier, which comprises carrying out the reaction in a polar aprotic ion-solvating solvent in the presence of a suitable compound of Na, K, Rb or Cs.
We have found that the process according to the invention permits access to a large number of compounds of the indole type of a range which has not been possible with the processes of the prior art. By using the alkali metal compounds which are employed in the process according to the invention, it is possible to prepare indole derivatives which may have virtually any customary substituents R
1
, R
2
. In the individual case, the accessibility of certain substituted indole derivatives depends on the influence of certain parameters. These are, for example, steric interactions between the individual substituents present, and possibly also the aromatic system is of the indole derivative. The range of the different substituents R
1
and R
2
and of the substituents which may be present on the aromatic system of the formula (I) is enormously wide and comprises virtually all compound classes and functional groups which are included in the definition given above.
In a preferred embodiment of the present invention, the substituents R
1
and R
2
independently of one another are selected from the group consisting of H, linear and branched C
1
-C
12
-alkyl groups, linear and branched C
2
-C
12
-alkenyl groups, C
3
-C
8
-cycloalkyl groups, C
3
-C
8
-cycloalkenyl groups, C
5
- and C
6
-heterocycles having one or more ring atoms selected from the group consisting of N, O and S and mono- or bicyclic aromatics having one or more ring atoms selected from the group consisting of N, O and S.
Both in the preferred and the not preferred embodiments, the substituents R
1
and R
2
may have one or more substituents in their molecular skeleton.
Examples of preferred substituents are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, thioether groups, amide and ester groups, sulfaryl groups and sulfoxide groups.
The aromatic system in the compounds of the formula (I) can be a mono- or polycyclic aromatic which comprises exclusively carbon and hydrogen or which may have one or more heteroatoms selected from the group consisting of N, O and S.
The aromatic system is preferably a mono- or bicyclic aromatic. More preferably, the aromatic system is a C
5
-heterocycle or a benzene or naphthalene derivative which may contain one or more of the heteroatoms N, O and S mentioned, examples being benzene and naphthalene, aza-, diaza- and triazabenzene, aza-, diaza- and triazanaphthalene, thiophene and furan.
In the most preferred embodiment of the present invention, the aromatic system in the formula (I) is selected from the group consisting of benzene, naphthalene, pyridine, pyrazine, pyrimidine, quinoline, thiophene and furan.
Both in the preferred and the not preferred embodiments, the aromatic system may have one or more substituents which, similarly to the substituents R
1
and R
2
, may vary extremely. Non-limiting examples of such substituents are alkanes and alkenes which are either unsubstituted or may carry customary substituents, for example halogens, amines, nitro groups, ether and hydroxyl groups or thiol- and thioether groups. Further examples of substituents on the aromatic system are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, sulfaryl groups, sulfoxide groups, thioether groups, amide and ester groups.
In one embodiment of the present invention, the synthesis of the indole derivatives (I) can be carried out by attaching the alkynylaminoaromatic (II) used as starting material to an organic or inorganic carrier and immobilizing it. These carriers are known to the person skilled in the art and correspond to the customary carrier materials used, for example, for solid-phase peptide synthesis or for fixing transition metal catalyst systems. Examples are Merrifield resin, 4-(2′, 4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucyl-methylbenzhydrylamino-(divinylbenzene-crosslinked polystyrene) resin, also known under the name Rink-MBHA resin, which is generally used after deprotection by removal of the 9-fluorenylmethoxycarbonyl-(Fmoc) group, and the carrier resin which is commercially available under the name trityl chloride resin, if appropriate after appropriate modification.
These carriers are either bonded to the aromatic system of the starting materials (II), or the substituent R
1
is attached to the carrier. If appropriate, the carrier may have suitable spacer g

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