PREPARATION OF AROMATIC CARBOXYAMIDES BY A PALLADIUM-CATALYZED CARBONYLATION REACTION

Abstract

The present invention relates to a process for the preparation of aromatic carboxyamides of formula I, which can be obtained by a palladium-catalyzed carbonylation reaction of aromatic chlorides of formula II, amines of formula III and carbon monoxide in the presence of 1,5,7-triazabi-cyclo[4.4.0]dec-5-ene. The invention further relates to a process for the preparation of aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are known for controlling phytopathogenic fungi.

##STR00001##

Claims

1. A process for preparing an aromatic carboxyamide of formula I, ##STR00014## wherein Aryl is phenyl or a 5- or 6-membered aromatic heterocycle; wherein the ring member atoms of the aromatic heterocycle include besides carbon atoms 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein Aryl is further unsubstituted or further substituted with additional n identical or different radicals R.sup.A; wherein n is 0, 1, 2, 3, or 4; R.sup.A is independently selected from the group consisting of fluorine, chlorine, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, —S(═O).sub.2—CH.sub.3, —O—C≡N, —S—C≡N, —N═C═O, —N═C═S, diC.sub.1-C.sub.6-alkylamino, —C(═O)—C.sub.1-C.sub.6-alkyl, —C(═O)—O—C.sub.1-C.sub.6-alkyl, and —CH.sub.2OH; R.sup.1 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.11-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.6-alkenyloxyimino-C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.6-alkynyloxyimino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkylamino, diC.sub.1-C.sub.6-alkylamino, —C(═O)—C.sub.1-C.sub.6-alkyl, —C(═O)—O—C.sub.1-C.sub.6-alkyl, C(═O)—N(C.sub.1-C.sub.6-alkyl).sub.2, phenyl-C.sub.1-C.sub.4-alkyl, phenyl-C.sub.1-C.sub.4-alkenyl, phenyl-C.sub.1-C.sub.4-alkynyl, heteroaryl-C.sub.1-C.sub.4-alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heteroaryl group in the group heteroaryl-C.sub.1-C.sub.4-alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocyclic ring include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different groups R.sup.1a; or R.sup.1 and R.sup.2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes beside one nitrogen atom and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R.sup.1a; wherein R.sup.1a is halogen, oxo, cyano, NO.sub.2, OH, SH, NH.sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, —NHSO.sub.2—C.sub.1-C.sub.4-alkyl, —(C═O)—C.sub.1-C.sub.4-alkyl, —C(═O)—O—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkylsulfonyl, hydroxyC.sub.1-C.sub.4-alkyl, —C(═O)—NH.sub.2, C(═O)—NH(C.sub.1-C.sub.4-alkyl), C.sub.1-C.sub.4-alkylthio-C.sub.1-C.sub.4-alkyl, aminoC.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, diC.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, aminocarbonyl-C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; R.sup.2 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.11-cycloalkyl, —C(═O)H, —C(═O)—C.sub.3-C.sub.11-cycloalkyl, or —C(═O)—O—C.sub.1-C.sub.6-alkyl; and wherein any of the aliphatic or cyclic groups in R.sup.2 are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-alkoxy, and C.sub.3-C.sub.11-cycloalkyl; the process comprising reacting an aromatic chloride of formula II,
Aryl-Cl   wherein Aryl is as defined above for compounds of formula I, with carbon monoxide and an amine compound of formula III, ##STR00015## wherein R.sup.1 and R.sup.2 are as defined above for compounds of the formula I; and wherein the reaction is carried out in the presence of a palladium-based catalyst, a solvent, and a base; and wherein the process is characterized in that the base is 1,5,7-triazabi-cyclo[4.4.0]dec-5-ene.

2. The process according to claim 1, wherein Aryl is phenyl.

3. The process according to claim 1, wherein the aromatic chloride is of formula II.b, ##STR00016## wherein n is 0 or 1 and R.sup.A is as defined in claim 1 for compounds of formula I to obtain an aromatic carboxyamide of formula I.b ##STR00017## wherein the variables n and R.sup.A have the meaning as defined for compounds II.b and wherein the variables R.sup.1 and R.sup.2 have the meaning as defined for compounds of formula I.

4. The process according to claim 1, wherein n is 0.

5. The process according to claim 1, wherein in compounds of formulae I and III R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl; and R.sup.2 is hydrogen, methyl, or ethyl.

6. The process according to claim 1, wherein in compounds of formulae I and III R.sup.1 is methyl or phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3, or 4 identical or different groups selected from halogen; and wherein R.sup.2 is hydrogen, methyl, or ethyl.

7. The process according to claim 1, wherein in compounds of formulae I and III R.sup.1 is methyl or 2-fluoro-phenyl; and wherein R.sup.2 is hydrogen.

8. The process according to claim 1, wherein the process is conducted at a temperature between 70° C. and 140° C.

9. The process according to claim 1, wherein the process is conducted at a pressure between 300 and 2000 kPa.

10. The process according to claim 1, wherein TBD is used in an amount of at least 80 mol % based on the amount of the compound of formula II.

11. The process according to claim 1, wherein the palladium-based catalyst is prepared from Pd(II) compounds or Pd(0) compounds by complexing with monodentate or bidentate phosphine ligands.

12. The process according to claim 1, wherein the palladium-based catalyst is prepared from Pd(II) compounds or Pd(0) compounds by complexing with monodentate or bidentate phosphine ligands selected from the group consisting of triphenylphosphine, tri(tolyl)phosphine, tri-n-butylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, S-phos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), cyclohexyldiphenylphosphine, tri-iso-propylphosphine, phenyldicycloheylphosphine, butyldiadamantylphosphine, 1,2-Bis(dimethylphosphino)ethane, 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 2-Bis(diphenylphosphino)ethane (DPPE), 1,3-Bis(diphenylphosphino)-propane (DPPP), 1,4-Bis(diphenylphosphino)butane (DPPB), 1,1′-Bis(diphenylphos-phino)ferrocene (DPPF), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), Bis(2-diphenylphosphino)phenyl] ether (DPEphos), 1,2-Bis(di-tert-butylphosphinomethyl)benzene, 1,2-Bis(di-tert-pentylphosphinomethyl)benzene, 1,2-Bis(di-tert-butylphosphinomethyl)naphthaline, 2,2-dimethyl-1,3-Bis(diphenylphosphino)-propane, 1,3-Bis(diisoproylphosphino)-propane (DiPrPP), 1,3-Bis(tert-butylphosphino)-propane (DtBuPP), 1,3-Bis(n-butylphosphino)-propane (DnBuPP), 1,3-Bis(diisoproylphosphino)-ethan (DOPE), 1,3-Bis(dicyclohexylphosphino)-butane (DCPB), (1R)-1-[Bis(1,1-dimethylethyl)phosphino]-2-[(1R)-1-[Bis(2-methylphenyl)phosphino]ethyl]ferrocene, (2R)-1-[(1R)-1-[Bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene, (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene, 2-ethyl-2-butyl-1,3-Bis(diphenylphosphino)-propane, and 1,3-Bis(dicyclohexylphosphino)-propane (DCPP); and wherein the molar ratio of the phosphine ligand to palladium is between 0.5:1 to 5:1.

13. The process according to claim 3, the process further comprising the step of reacting the compound of formula I.b to obtain a compound of formula IV ##STR00018##

14. The process according to claim 13, further comprising reacting the compound of formula IV to obtain a compound of formula V ##STR00019##

15. The process according to claim 14, further comprising reacting the compound of formula V to obtain a compound of formula VI ##STR00020##

Description

WORKING EXAMPLES

[0112] The present invention is further illustrated by means of the following working examples.

Example 1

Preparation of 4-cyano-N-(2-fluoro-phenyl)-benzamide

[0113] Palladium(II)chloride (4.1 mg, 0.023 mmol), 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (12.5 mg, 0.020 mmol), TBD (1.1 g, 8.0 mmol) and 4-chlorbenzonitril (1.09 g, 8.0 mmol) were kept under argon in an autoclave. 2-Fluoroanilin (1.67 g, 15 mmol) and tetrahydrofurane (10 mL) were added under argon and carbon monoxide was introduced into the reaction vessel at a pressure of 10 bar (1000 kPa). The reaction mixture was stirred at 130° C. for 20 hours (stirring rate 1000 rpm). Then, the reaction mixture was cooled to room temperature followed by the release of the pressure. GC-conversion*: 96%; selectivity regarding carboxyamide: 99%.

[0114] *Analytical GC method: VF-23 column (60 m×0.25 mm/0.25 μm; temperature: 2 min at 50° C., then 10° C./min up to 100° C.; then 15° C./min up to 200° C.; 5 min at 200° C.; then 20° C./min up to 250° C.; flow: 2.0 mL/min; hydrogen as carrier gas). t.sub.R (2-fluoroaniline)=10.9 min; t.sub.R (4-chlorobenzonitrile)=12.5 min; t.sub.R (carboxyamide)=34.3 min.

[0115] Table 1 provides the results of experiments with variations to the reaction conditions of Example 1 above. [Comment on results]

[0116] Except otherwise noted each of the Examples 1, 1.1, 1.2, 1.6 of Table 1 represents variations according to the present invention, as the reaction is carried out using TBD as base with various Pd-sources.

[0117] Examples 1.3 to 1.5 of Table 1 represent comparative examples showing that at the chosen conditions (at low catalyst loadings of 0.25 mol % Pd), the reaction with TBD proceeds much faster after 20 h reaction compared to the case when TBD is replaced by an equimolar amount of another base.

TABLE-US-00001 TABLE 1 Conversion Pd source Ligand Base after reaction Selectivity Example (mol %) (mol %) (mol %) time amide (GC*)  1 .sup.a), b) PdCl.sub.2 DCPP*HBF.sub.4 TBD 96% 99% (0.25) (0.25) (100) 1.1 .sup.b) 10% Pd/C DCPP*HBF.sub.4 TBD 96% 98% (0.25) (0.25) (100) 1.2 .sup.b) Pd(OH).sub.2 DCPP*HBF.sub.4 TBD 95% 98% (0.25) (0.25) (100) 1.3 .sup.c) PdCl.sub.2 DCPP*HBF.sub.4 K.sub.2CO.sub.3 45% 95% (0.25) (0.25) (100) 1.4 .sup.c) PdCl.sub.2 DCPP*HBF.sub.4 DBU 42% 99% (0.25) (0.25) (100) 1.5 .sup.c) PdCl.sub.2 DCPP*HBF.sub.4 triethylamine  0% — (0.25) (0.25) (100) 1.6 .sup.b) PdCl.sub.2 — TBD 95% 98% DCPP (100) (0.25) .sup.a) identical with example 1 above; .sup.b) example representing the present invention, identical with example 1 unless otherwise mentioned in table 1 .sup.c) comparative example not according to the invention, identical with example 1 unless otherwise mentioned in table 1

Example 2

Preparation of N,N-diethyl-3,5-dimethyl-benzamide

[0118] Palladium(II)chloride (57 mg, 0.32 mmol, 4 mol %), 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (197 mg, 0.32 mmol, 4 mol %), TBD (1.1 g, 8.0 mmol) and 5-Chlor-m-xylol (1.13 g, 8.0 mmol) were kept under argon in an autoclave. Diethylamine (2.93 g, 40 mmol) and N-methylpyrrolidine (15 mL) were added under argon and carbon monoxide was introduced into the reaction vessel at a pressure of 10 bar (1000 kPa). The reaction mixture was stirred at 130° C. for 20 hours (stirring rate 1000 rpm). Then, the reaction mixture was cooled to room temperature followed by the release of the pressure. GC-conversion*: 73%; selectivity regarding carboxyamide: 87%.

[0119] Table 2 provides the results of experiments with variations to the reaction conditions of Example 2 above. Example 2 of Table 2 represents reaction conditions (using a different aryl halide/amine combination compared to table 1) according to the present invention, as the reaction is carried out using TBD as base. Example 2.1 is a comparative example not representing the invention. Also in this case the reaction with TBD proceeds faster after 20 h reaction time compared to the case when TBD is replaced by an equimolar amount of potassium carbonate.

TABLE-US-00002 TABLE 2 Conversion Selectivity Pd source Ligand Base after reaction amide Example (mol %) (mol %) (mol %) time (GC*) 2 .sup.a)   PdCl.sub.2 DCPP*HBF.sub.4 TBD 73% 87% (4) (4) (100) 2.1 .sup.b) PdCl.sub.2 DCPP*HBF.sub.4 K.sub.2CO.sub.3 47% 70% (4) (4) (100) .sup.a) example representing the present invention, identical with example 2 unless otherwise mentioned in table 2; .sup.b) comparative example not according to the invention; carried out as example 2, TBD was replaced with potassium carbonate.

Example 3

Preparation of Methyl 4-((2-fluoro-phenyl)carbamoyl) benzoate

[0120] Palladium(II)chloride (7.8 mg, 0.044 mmol), 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (25 mg, 0.041 mmol), TBD (1.1 g, 8.0 mmol) and Methyl-4-chlorbenzoat (1.41 g, 8.27 mmol) were transferred into a glass autoclave under argon atmosphere. 2-Fluoroanilin (1.69 g, 15 mmol) and tetrahydrofurane (15 mL) were added under a constant argon flow. The autoclave was pressurized with 10 bar (1000 kPa) of carbon monoxide. The reaction mixture was stirred at 130° C. for 20 hours (stirring rate 1000 rpm). Then, the reaction mixture was cooled to room temperature followed by the release of the pressure. GC-conversion*: 84%; selectivity regarding carboxyamide: 52%.

[0121] Table 3 provides the results of experiments with variations to the reaction conditions of Example 3 above.

[0122] Example 3 of Table 3 represents reaction conditions (using a different aryl halide/amine combination compared to table 1) according to the present invention, as the reaction is carried out using TBD as base. Example 3.1 is a comparative example not representing the invention. As in the other examples, also in this case the reaction with TBD proceeds much faster after 20 h reaction time compared to the case when TBD is replaced by an equimolar amount of potassium carbonate.

TABLE-US-00003 TABLE 3 Conversion Selectivity Pd source Ligand Base after reaction amide Example (mol %) (mol %) (mol %) time (GC*) 3 .sup.a)   PdCl.sub.2 DCPP*HBF.sub.4 TBD 84% 52% (0.5) (0.5) (100) 3.1 .sup.b) PdCl.sub.2 DCPP*HBF.sub.4 K.sub.2CO.sub.3  0% — (0.25) (0.25) (100) .sup.a) identical with example 3 above; .sup.b) comparative example not according to the invention; TBD was replaced with potassium carbonate.