PREPARATION OF AROMATIC CARBOXYAMIDES BY PALLADIUM-CATALYZED CARBONYLATION REACTION

Abstract

Preparation of aromatic carboxyamides by palladium-catalyzed carbonylation reaction The present invention relates to a process for the preparation of aromatic carboxyamides of formula I, which can be obtained by palladium-catalyzed carbonylation reaction of aromatic chlorides of formula II, amines of formula III and carbon monoxide in the presence of a base. 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.1-cycloalkyl, —C(═O)H, —C(═O)—C.sub.1-C.sub.6-alkyl, —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  II 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 comprises a base b1 and a base b2, wherein b1 is at least one inorganic base selected from the group consisting of alkali metal and alkaline earth metal carbonates, hydrogen carbonates, acetates, alcoholates, hydroxides, and phosphates, or mixtures thereof; b2 is a tertiary amine base or an imine base, which is present in an amount of less than 100 mol % based on the amount of the compound of formula II.

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 above 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 above 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 Ill 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 Ill 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 base b1 is an alkali metal carbonate or an alkali metal acetate.

9. The process according to claim 1, wherein the base b1 is used in an amount that ranges between 90 and 150 mol %, based on the aromatic chloride of formula II.

10. The process according to claim 1, wherein the base b2 is an amine selected from the group consisting of DABCO, N-methylpiperidine, lutidine, pyridine, and a base of the formula B.2, ##STR00018## wherein X is NR.sup.4R.sup.5 or C.sub.1-C.sub.4-alkyl; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 independently of each other are hydrogen or C.sub.1-C.sub.4-alkyl; or R.sup.1 and R.sup.2 together with the interjacent atoms between these radicals form a 5-, 6- or 7-membered ring, which contains besides carbon atoms 2 nitrogen atoms; or, if X is NR.sup.4R.sup.5, R.sup.3 and R.sup.4 together with the interjacent atoms between these radicals form a 5-, 6- or 7-membered ring, which contains besides carbon atoms 1 or 2 nitrogen atoms; or, if X is C.sub.1-C.sub.4-alkyl, R.sup.3 and X together with the interjacent atoms between these radicals form a 5-, 6- or 7-membered ring, which contains besides carbon atoms 1 or 2 nitrogen atoms.

11. The process according to claim 1, wherein the base b2 is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

12. The process according to claim 1, wherein the base b2 is used in an amount that ranges between 1 and 20 mol %, based on the aromatic chloride of formula II.

13. The process according to claim 1, wherein the process is conducted at a temperature between 50° C. and 150° C.

14. The process according to claim 1, wherein the process is conducted at a pressure between 500 and 1500 kPa.

15. 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.

16. 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 (DCPE), 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.

17. The process according to claim 3, the process further comprising reacting the compound of formula I.b to obtain a compound of formula IV ##STR00019##

18. The process according to claim 17, further comprising reacting the compound of formula IV to obtain a compound of formula V ##STR00020##

19. The process according to claim 18, further comprising reacting the compound of formula V to obtain a compound of formula VI ##STR00021##

Description

WORKING EXAMPLES

[0153] The present invention is further illustrated by means of the following working examples.

Example 1) Preparation of 4-cyano-N-(2-fluoro-phenyl)-benzamide (Example not According to the Invention)

[0154] Palladium(II)chloride (3.8 mg, 0.021 mmol), 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (DCPP*HBF.sub.4, 12.9 mg, 0.021 mmol), potassium carbonate (1.12 g, 8.1 mmol) and 4-chlorobenzonitrile (1.12 g, 8.1 mmol) were kept under argon in an autoclave. 2-Fluoroaniline (1.74 g, 15.7 mmol) and tetrahydrofuran (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*: 45%; selectivity regarding carboxyamide: 95%.

[0155] Except otherwise noted each of the Examples 2, 3, 1.1 to 1.6 of Table 1 below reproduced the same reaction conditions as Example 1 above. Examples 1.1 to 1.6 represent variations according to the present invention, as they included catalytic amounts of DBU, based on the amount of 4-chlorobenzonitrile, in addition to stoichiometric amounts of a base of type b1.

[0156] It was observed that, at low catalyst concentration, the reaction eventually stopped and did not achieve desirable degrees of conversions (Example 1, the catalyst composition leads to conversions of 45% after 20 hours reaction time). If the reaction time was prolonged to 40 hours, 72% conversion was observed under these conditions (Example 2). Example 3 illustrates that equimolar amounts of DBU based on the amount of 4-chlorobenzonitrile, and in the absence of a base of type b1, did not lead to an increase in conversion after 20 hours.

[0157] It was surprisingly found that upon addition of catalytic amounts of a base b2 (DBU, 5 mol %) significantly higher conversions were achieved (Examples 1.1 and 1.2). Example 1.2 shows that a prolongation of the reaction time to 40 hours leads to 88% conversion as compared to 72% conversion in Example 2. Examples 1.3 to 1.5 illustrate that different Pd and ligand sources were successfully used. Example 1.6 shows that potassium carbonate (base b1) could be exchanged with another base.

TABLE-US-00001 TABLE 1 Conversion Pd Ligand DBU Reaction after reaction Selectivity Example (mol %) (mol %) (mol %) time (hours) time amide (GC*) 1 .sup.a), b) PdCl.sub.2 DCPP*HBF.sub.4 — 20 45% 95% (0.25) (0.25) 2 .sup.b) PdCl.sub.2 DCPP*HBF.sub.4 — 40 72% 95% (0.25) (0.25) 3 .sup.b), e) PdCl.sub.2 DCPP*HBF.sub.4 100 20 42% 99% (0.25) (0.25) 1.1 .sup.c) PdCl.sub.2 DCPP*HBF.sub.4 5 20 76% 98% (0.25) (0.25) 1.2 .sup.c) PdCl.sub.2 DCPP*HBF.sub.4 5 40 88% 96% (0.25) (0.25) 1.3 .sup.c) Pd/C .sup.d) DCPP*HBF.sub.4 5 20 89% 98% (0.25) (0.25) 1.4 .sup.c) Pd(OH).sub.2 DCPP*HBF.sub.4 5 20 82% 98% 0.25) (0.25) 1.5 .sup.c) PdCl.sub.2 — 5 20 71% 96% DCPP (0.25) 1.6 .sup.c), f) PdCl.sub.2 DCPP*HBF.sub.4 5 20 76% 97% (0.25) (0.25) .sup.a) identical with Example 1) above; .sup.b) example not according to the invention; .sup.c) example representing the present invention; .sup.d) Pd(10%) on charcoal, mol % relates to the molar amount of Pd; .sup.e) no potassium carbonate present; .sup.f) sodium carbonate was used instead of potassium carbonate *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.