# US 6,297,270 B1 · Process for the preparation of 2,3-Dihydroindoles (indolines), novel 2,3-dihydroindoles, and their use

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- Number: US 6,297,270 B1
- Document ID: US6297270B1
- Status: Granted
- Kind: B1
- Application number: 09/442,615
- Filed: 1999-11-18
- Granted: 2001-10-02
- Earliest claimed: 1998-11-20
- Assignees: Aventis Research & Technologies GmbH & Co. KG
- Inventors: Matthias Beller; Thomas Riermeier; Harald Trauthwein; Claudia Breindl
- Web page: https://patentgrep.com/patent/US6297270B1

## CPC

- A01N 43/38: condensed with carbocyclic rings
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07F 7/083: {Syntheses without formation of a Si-C bond}
- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A process for the preparation of 2,3-dihydroindoles of the formula (I) by reaction of halostyrenes of the formula (IIa) or (IIb) with amines of the formula (III) R1—NH2 (III) in at least one inert solvent or in water, and in the presence of at least one base.

## Claims

### Claim 1

A 2,3-dihydroindole which is selected from the group consisting of N-(4-fluorophenyl)-4-chloro-2,3-dihydroindole, N-(4-fluorophenyl)-2,3-dihydroindole and N-(3-ethoxypropyl)-2,3-dihydroindole.

### Claim 2 (depends on 1)

A ligand metal catalyst wherein the ligands are a 2,3-dihydroindole according to claim 1.

### Claim 3 (depends on 1)

A cosmetic or oral hygiene composition which comprises the cosmetic or oral hygiene product and a 2,3-dihydroindole in claim 1 as an antioxidant.

### Claim 4 (depends on 1)

A flame-retardant additive which comprises a 2,3-dihydroindole according to claim 1.

### Claim 5 (depends on 1)

A method for killing unwanted plant growth which comprises applying a 2,3-dihydroindole as claimed in claim 1 to said plant or to an area where it resides.

### Claim 6 (depends on 1)

A plastic which comprises a 2,3-dihydroindole according to claim 1 as a stabilizing agent or an antistatic agent.

### Claim 7 (depends on 1)

A method for inhibiting angiotensin (II) in a host in need thereof which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 8 (depends on 1)

A method for inhibiting lipoxygnase in a host in need thereof, which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 9 (depends on 1)

A method for blocking a calcium channel in a host in need thereof, which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 10 (depends on 1)

A method for treating depression in a host in need thereof, which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 11 (depends on 1)

A method for treating Alzheimer's disease to a host in need thereof, which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 12 (depends on 1)

A method for inhibiting protein kinase in a host in need thereof, which comprises administering a 2,3-dihydroindole according to claim 1 to said host.

### Claim 13 (depends on 1)

In a method for preparing polyesters, the improvement which comprises adding a 2,3-dihydroindole according to claim 1 as a polymerization catalyst.

### Claim 14 (depends on 1)

A method for stabilizing a plastic which comprises adding a 2,3-dihydroindole according to claim 1 to said plastic.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the plastic is a PVC or a polyamide.

### Claim 16 (depends on 1)

A method for reducing the static in a plastic which comprises adding a 2,3-dihydroindole according to claim 1 as an antistatic agent to said plastic.

### Claim 17

A process for the preparation of 2,3-dihydroindoles of the formula (I)
in which the radicals R1 to R7 independently of one another are selected from the group consisting of hydrogen, fluorine, chlorine, (C1-C8)-alkyl, O-alkyl-(C1-C8), OCO-alkyl-(C1-C8), OH, NO2, Si(alkyl)3-(C1-C8), CF3, CN, COOH, CHO, SO3H, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), NH—Ar, NAr2, P-alkyl2-(C1-C8), SO2-alkyl-(C1-C6), SO-alkyl-(C1-C6), NHCO-alkyl-(C1-C4), COO-alkyl-(C1-C8), CONH2, CONH-alkyl-(C1-C8), CO-alkyl-(C1-C8), NHCOH, NHCOO-alkyl-(C1-C4), CHCH—CO2-alkyl-(C1-C8), CHCHCO2H, P-alkyl2-(C1-C8), POalkyl2-(C1-C4), PO3H2, PO(O-alkyl-(C1-C6))2, SO3-alkyl-(C1-C4), SO2-alkyl-(C1-C6), SO-alkyl-(C1-C6), Si(alkyl)3-(C1-C8), Ar, O—Ar, CO—Ar, COO—Ar, PO—Ar2 and PAr2;
where Ar is
an aromatic radical having up to 14 carbon atoms; or
a heteroaromatic, selected from the group consisting of the five-, six- or seven-membered rings having at least one nitrogen, oxygen and/or sulfur atom in the ring;
by reaction of halostyrenes of the formula (IIa) or (IIb)
with amines of the formula (III)
R1—NH2 (III)
where in the formulae (IIa), (IIb) and (III)
R1 to R7 have the same meaning as in formula (I);
X is selected from the group consisting of chlorine, bromine, iodine, OSO2CF3, OSO2aryl-(C6-C10), OSO2alkyl-(C1-C8) and N2+Y−, where Y is a chlorine, bromine or iodine atom or a tetrafluoroborate or tetraphenylborate anion;
in at least one inert solvent or in water and in the presence of at least one base, selected from the group consisting of
primary, seconary and tertiary alkoxides;
primary and secondary amides of alkali metal and/or alkaline earth metal elements;
alkyl and aryl compounds of alkali metals and/or alkaline earth metals; and
carbonates, hydroxides, hydrogencarbonates of lithium, sodium, potassium, calcium, magnesium and cesium.

### Claim 18 (depends on 17)

The process as claimed in claim 17, wherein the radical R1 is a (C1-C8)-alkyl, phenyl, naphthyl, anthryl, phenanthryl, biphenyl, pyridine, pyrimidine, oxazole, imidazole, pyrazine, quinoline, indole, furan, benzofuran or thiophene radical.

### Claim 19 (depends on 1, 17)

The process as claimed in claim 17, wherein the radicals R2 to R7 independently of one another are selected from the group consisting of hydrogen, (C1-C8)-alkyl, O-alkyl-(C1-C8), OCO-alkyl-(C1-C8), N-alkyl2-(C1-C8), Ar, F, Cl, NO2, CN, COOH, CHO, SO2-alkyl-(C1-C4), NH-alkyl-(C1-C8), NH—Ar, NAr2, COO-alkyl-(C1-C8), CONH2, CONH-alkyl-(C1-C8), CO-alkyl-(C1-C8), CO—Ar and/or PO—Ar2; where Ar has the same meaning as in claim 1 and is in particular a phenyl radical.

### Claim 20 (depends on 1, 17)

The process as claimed in claim 17, wherein
the aromatic radical Ar has up to 5 substituents;
the heteroaromatic has up to 4 substituents; and/or
the radical R1 has up to 5 substituents,
which independently of one another are selected from the group consisting of fluorine, chlorine, CF3, OH, NO2, CN, R5, O—R5, CHO, CO—R5, COOH, COO—R5, OCO—R5, SiR53, NH2, NH—R5, N—R52, SO—R5, SO2—R5, SO3H, SO3—R5, CONH2, NHCOH, NHCO—R5, NHCOO—R5, CHCH—CO2-alkyl-(C1-C8), PO—R52, P—R52, PO3H2, PO(O-alkyl-(C1-C6))2 and CHCHCO2H; where R5 is an alkyl radical having 1 to 8 carbon atoms or an aryl radical Ar; where Ar has the same meaning as in claim 1 and is in particular a phenyl radical.

### Claim 21 (depends on 17)

The process as claimed in claim 17, wherein R1 is a 4-fluorophenyl or 2-methoxyphenyl radical.

### Claim 22 (depends on 17)

The process as claimed in claim 17, wherein the radical Ar is a heteroaromatic to whose heteroaromatic ring up to four further aromatic, heteroaromatic and/or aliphatic rings are fused.

### Claim 23 (depends on 17)

The process as claimed in claim 17, wherein the base is selected from the group consisting of potassium alkoxides, cesium alkoxides, alkali metal amides, organolithium compounds and organomagnesium compounds.

### Claim 24 (depends on 23)

The process as claimed in claim 23, wherein the base is selected from the group consisting of potassium tert-butoxide, potassium isopropoxide, sodium methoxide, potassium methoxide, sodium ethoxide, magnesium methoxide, calcium ethoxide, lithium diisopropylamide, lithium diethylamide, sodium dimethylamide, cesium carbonate, butyllithium, phenyllithium, phenylmagnesium chloride and potassium hydroxide.

### Claim 25 (depends on 17)

The process as claimed in claim 17, wherein the inert solvent is selected from the group consisting of aromatic or aliphatic hydrocarbons, esters, amines and amides.

### Claim 26 (depends on 25)

The process as claimed in claim 25, wherein the solvent is selected from the group consisting of THF, dioxane, diethyl ether, diglyme, MTBE, DME, toluene, xylenes, anisole, ethyl acetate, ethylene carbonate and propylene carbonate.

### Claim 27 (depends on 17)

The process as claimed in claim 17, wherein the base is employed in an amount from 0.5 to 10 equivalents, based on the halostyrene of the formula (IIa) or (IIb).

### Claim 28 (depends on 27)

The process as claimed in claim 27, wherein the base is employed in an amount from 0.8 to 5 equivalents, based on the halostyrene of the formula (IIa) or (IIb).

### Claim 29 (depends on 17)

The process as claimed in claim 17, wherein the reaction is carried out at a temperature between 0 and 200° C., preferably between 40 and 180° C., in particular between 60 and 160° C.

### Claim 30 (depends on 17)

The process as claimed in claim 17, wherein the reaction is carried out in the presence of an additional dehydrogenating agent.

### Claim 31 (depends on 17)

The process as claimed in claim 17, wherein a dehydrogenating agent is added to the reaction mixture after reaction has taken place.

### Claim 32 (depends on 30)

The process as claimed in claim 30, wherein the dehydrogenating agent is selected from the group consisting of oxygen, sulfur and DDQ.

### Claim 33 (depends on 1)

In a process for preparing a dye, amino acid, a photosensitive and/or thermosensitive material, or a cosmetic, the improvement which comprises using a 2,3-dihydroindole as claimed in claim 1 in said process.