Process for the preparation of substituted 3-aminobenzonitriles

Details Process for the preparation of substituted 3-aminobenzonitriles Process for the preparation of substituted 3-aminobenzonitriles

1997-08-01

1999-03-16

Richter, Johann

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

Organic compounds

Nitriles

558414, 558423, C07C25550, C07C25558

Patent

active

058832831

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/03936 Oct. 5, 1995.
The invention relates to a process for the preparation of substituted 3-aminobenzonitriles of the formula I ##STR1## in which: R is hydrogen or C.sub.1 -C.sub.12 alkyl, C.sub.3 -C.sub.8 cycloalkyl, COR.sub.1, C.sub.1 -C.sub.8 alkoxyalkyl, -C.sub.8 alkyl-NH(C.sub.1 -C.sub.4 alkyl), unsubstituted benzyl; and substituted 3-aminochlorobenzene of the formula II ##STR2## in which R is as defined for formula I with a cyano-donating reagent selected from amongst complexing agent; or a complexing agent; or ketone HCN adduct or aldehyde HCN adduct, in the presence of a catalyst NiL.sub.2 Hal.sub.2, excess L and a reducing agent, M being an alkali metal, L being a ligand and n being 2 to 4.
The general terms used hereinabove and hereinbelow have the following meanings, unless otherwise defined: carbon atoms, and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1-hexyl or 3-hexyl.
Depending on the size of the ring, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The ligands are phosphine groups PQ.sub.3 in which aryl or aryl which is substituted by alkoxy, di(C.sub.1 -C.sub.4 alkyl)amino(C.sub.1 -C.sub.4)alkyl, fluorine, unsubstituted ferrocenyl or ferrocenyl which is substituted by one of the radicals mentioned for "aryl". Preferred ferrocenyl ligands are the unsubstituted ferrocenyl and the asymetrical monosubstituted representatives, for example 1 -hydroxyethylferrocene and 1-dimethylaminoethylferrocene. Preferred catalysts are those of the formula Ni.sup.o --L.sub.n in which L is triphenylphosphine and n is 2 to 4, or those of the formula Ni.sup.o --L.sub.2 in which L is (1,1'-bisdiphenylphosphine-1-(dimethylaminoethyl)ferrocene).
The compounds of the formula I are important intermediates in the preparation of the compound of the formula III and of its acid derivatives which have been disclosed as plant immunization agents and plant conditioners (cf. EP-B-313 512). ##STR3##
The process according to the invention comprises reacting a substituted 3-aminochlorobenzene of the formula II with a cyanide to give the compounds of the formula I according to the invention: ##STR4##
The exchange of halogen for the cyano group on aromatic compounds by CuCN or by complex metal cyanides, for example potassium cyanoferrate(II) Braun synthesis"; for example Houben-Weyl, Methoden der organischen Chemie 1985).
It is also known that aromatically bonded halides can be replaced by the cyano group by means of a cyano-donating compound, for example alkali metal cyanide, HCN, Ni(CN).sub.2 or tetramethylsilyl cyanide, or ketone HCN adduct or aldehyde HCN adduct, in the presence of a Co, Pd or Ni catalyst (for example "Homogeneous Catalysis II" Adv. Chem. Ser. 132 ACS 1974 p. 252; Coll. Czechoslovak Chemm. Commun. Vol. 48 (1983) p. 1765).
The conversion of sulfur-containing chloroanilins with the specific 1,2,3 arrangement into the desired nitriles is novel. The surprising aspect is that this reaction proceeds with good selectivity and a high yield without substantial cleavage of a carbon-sulfur bond being observed. Moreover, it could not have been expected that this reaction proceeds readily in an electron-rich system (both the sulfur and the amino group on the phenyl ring are electron-donating substituents). It is furthermore surprising that even large groups, for example tert-butylthio, isopropylthio and cyclohexylthio, in the ortho-position relative to the reaction centre do not impede the reaction to a considerable extent.
Reactions a) and b) are carried out in the presence of a complexing agent.
This complexing agent causes on the one hand an acceleration of the Cl/CN exchange reaction, and, on the other hand, suppresses cleavage of the S--R bond.
The complexing agent is a nitrogen-containing, electron-donating compound, for example pyridine, quinoline or isoquinoline, which are unsubstituted or mono- to trisubstituted by C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkox

REFERENCES:
Harris, Neil V. et al., Antifolate and Antibacterial Activities of 5-Substituted 2,4-Diaminoquinazolines, J. Med. Chem. vol. 33, 434-444, Dec. 1990.

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