Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1993-07-01
2001-03-20
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06204397
ABSTRACT:
The invention relates to a new process for the preparation of 3-substituted 4-cyano-pyrrole compounds which may be used as pesticides.
It is known that fungicidally active 3-aryl-4-cyano-pyrrole compounds are obtainable when the correspondingly substituted cinnamonitriles are reacted with p-toluenesulphonylmethyl isocyanide (TOSMIC) in the presence of sodium hydride (compare DE-OS (German Published Specification) 29 27 480 or Tetrahedron Lett. 52, 5337 [1972]). However, this process with yields of approximately 35-45% only gives unsatisfactory results. Also it is disadvantageous that the compounds thus obtainable must be laboriously purified (compare JP 61 30 571). Finally, both the reagents sodium hydride and p-toluenesulphonylmethyl isocyanide (TOSMIC) are not very well suited for technical syntheses, the first because of the high susceptibility to hydrolysis, and the associated fire risk from the gaseous hydrogen liberated during hydrolysis, and the second because of the easy decomposability at elevated temperature (compare EP 174 910).
No better suited for industrial syntheses is the n-butyllithium used as base in an analogous process (compare EP 333 661), which is also very susceptible to hydrolysis and is moreover laborious and expensive to prepare. The use of other bases is described, but with these also only unsatisfactory conversions are achieved (compare e.g. EP 310 558 or EP 206 999).
It is further known that the cinnamonitriles required for the synthesis of 3-aryl-4-cyano-pyrrole compounds are obtained by processes disclosed in the literature, as for example by a WITTIG reaction (compare e.g. Tetrahedron 41, 1259 [1985] or J. Amer. Chem. Soc. 83, 1733 [1961] or Synthesis 1977, 126) or by the KNOEVENAGEL condensation (compare e.g. Tetrahedron 43, 537 [1987] or Tetrahedron Lett. 1979, 553 or EP 378 046) from benzaldehydes. However, the synthesis of the benzaldehydes required for this is extraordinarily difficult, laborious and proceeds via many stages (compare e.g. EP 61 907 or JP 60 38 336 or EP 333 658).
The large-scale preparation of the 3-substituted 4-cyano-pyrrole compounds desired as fungicidally active end products via the literature-disclosed route of the &agr;-substituted cinnamonitriles (compare e.g. DE-OS (German Published Specification) 37 18 375 or DE-OS (German Published Specification) 38 00 387 or EP 324 336 or EP 378 046) fails finally because first these benzaldehydes, which are very difficult to synthesise, are required as starting compounds.
The alternative preparation of the cinnamonitriles required as precursors, from corresponding aromatic amines by MEERWEIN arylation gives very poor yields, particularly in the case of the desired 2,3-disubstituted aryl compound (compare EP 318 704 or EP 206 999 or J. Org. Chem 34, 714 [1969]).
Finally it is known that the cinnamonitriles required as precursors may also be obtained when bromides or iodides are reacted with acrylonitrile in the presence of a palladium catalyst and a phosphine as reaction auxiliary in basic or dipolar-aprotic solvents such as for example triethylamine or dimethylformamide (compare e.g. EP 78 768 or U.S. Pat. No. 4,820,835 or J. Chem. Soc., Perkin Trans. 1, 2597 [1987] or J. Organomet. Chem. 258, 101, [1983]). However, this reaction also fails in the case of the 2,3-disubstituted aryl compounds. Under the reaction conditions disclosed in the literature only a low conversion to the desired end product was achieved (compare the Preparation Example III-1).
It has now been found that the 3-substituted 4-cyano-pyrrole compounds of the general formula (I),
in which
Ar represents an at least 2,3-disubstituted aryl radical or substituted heteroaryl radical,
are obtained by reaction of bromides of the formula (II),
Ar—Br (II)
in which
Ar has the meaning given above,
in a first stage with acrylonitrile in the presence of a suitable solvent and a suitable reaction auxiliary, and of the aryl-acrylonitrile derivatives thus obtainable of the formula (III),
Ar—CH═CH—CN (III)
in which
Ar has the meaning given above,
in a second stage with phenylsulphonylmethyl isocyanides of the formula (IV),
Ph—SO
2
—CH
2
—NC (IV)
in which
Ph represents optionally substituted phenyl,
in the presence of a suitable diluent and optionally in the presence of a suitable reaction auxiliary, in especially favourable manner, particularly in high purity and high yield, by a process which is characterised in that the first stage is carried out in the presence of a palladium catalyst and the second stage in the presence of a 1.2- to 1.8-fold molar excess of alkali metal alcoholate or alkali metal hydroxide as base to give the acrylonitrile derivative.
Surprisingly, in the process according to the invention, the conversion of the acrylonitrile derivatives of the formula (III) with phenylsulphonyl-methyl isocyanides of formula (IV) in the second stage in the presence of a 1.2- to 1.8-fold molar excess of alkali metal alcoholate or alkali metal hydroxide as base succeeds in very high yields, although it was known from the prior art that weaker bases than sodium hydride, that is including alkali metal alcoholates or alkali metal hydroxides, give only poor yields (compare e.g. EP 310 558 or EP 206 999).
The use of an excess of base was also countered by the assumption that such an excess of base in the reaction mixture could react with the starting materials used as well as with the end product and that these side reactions would lead to undesired by-products and to a marked reduction in yield of the desired end product. (For side reactions of base and Tosmic compare e.g. Tetrahedron Lett. 1972, 2363-2368; Angew. Chem. 83, 357-358 [1971]; Angew. Chem. 86, 878ff [1974]; for side reactions of base and acrylonitrile in the presence of pyrrole, compare e.g. Liebigs Ann. Chem. 615, 124 [1958]; J. Chem. Soc. 1962, 4346.)
Further, it is surprising that the conversion of the bromides of formula (II) with acrylonitrile in the presence of palladium in the first stage of the process according to the invention, without the literature described addition of phosphines, as reaction auxiliaries, gives very high yields, especially as the reaction conditions described in the literature (compare e.g. EP 78 768 or U.S. Pat No. 4,820,835 or J. Chem. Soc., Perkin Trans 1, 1987 2597 or J. Organomet. Chem. 258, 101, [1983]) fail in the case of aryl compounds at least 2,3-disubstituted in the aryl part, which are of particular interest as fungicides; under the conditions described in the literature, almost no reaction occurs.
The process according to the invention has a number of advantages over the previously known processes:
For example, avoidance of phosphines as reaction auxiliaries in the first stage means that there are considerably fewer effluent problems, since phosphines and their reaction products—including in particular phosphine oxides—may be removed only with difficulty from the resulting effluent on account of their high water solubility.
A further advantage is the avoidance in the second stage of sodium hydride, which is difficult to handle industrially and requires complicated safety precautions. The alkali metal alcoholates or alkali metal hydroxides used as bases in the process according to the invention are cheap to prepare, simple to handle and harmless from the safety aspect.
It was further known from the prior art that the phenylsulphonylmethyl isocyanide may be replaced by substituted phenylsulphonylmethyl isocyanides such as 4-chlorophenyl- or 4-methylphenylsulphonylmethyl isocyanide. However, it was not previously known that the substituted compounds bring additional advantages. Thus the 4-chlorophenyl compound displays a low thermo—lability, which widens the safety margins, and can be used more economically with respect to its preparation and recovery from its reaction end products (sodium or potassium p-chlorophenylsulphinate). The 4-methylphenyl compound is also usable here, si
Andres Peter
Jelich Klaus
Knuppel Peter C.
Lantzsch Reinhard
Marhold Albrecht
Bayer Aktiengesellschaft
Norris & McLaughlin & Marcus
Trinh Ba K.
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