Synlett 2013; 24(9): 1150-1154
DOI: 10.1055/s-0033-1338433
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Tetrasubstituted Pyrazoles through Different Cyclization Strategies; Isosteres of Imidazole Fungicides

Raphael Dumeunier*
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Clemens Lamberth*
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Stephan Trah
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
› Author Affiliations
Further Information

Publication History

Received: 07 March 2013

Accepted after revision: 28 March 2013

Publication Date:
18 April 2013 (online)


Abstract

Formerly unknown 3-chloro-4,5-diaryl-1-methylpyrazoles have been prepared through two different synthesis pathways, one of which starts from 2,3-diarylacrylonitriles, the second from 3,3-dichloro-1,2-diarylpropenones. Both approaches rely on the cyclocondensation of diarylated three-carbon synthons with hydrazine derivatives and possess some unique features. One route uses a cyclization reaction, during which a chlorine atom is directly installed at the pyrazole ring that normally would be introduced in subsequent halogenation steps. The second pathway applies the Sandmeyer reaction to introduce this chloro substituent; an approach that is rarely described at the pyrazole nucleus. The obtained tetrasubstituted pyrazoles are isosteres of highly active imidazole fungicides and show good control of Uncinula necator (grape powdery mildew).

 
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  • 17 Typical Procedures:
    (Z)-3-(4-Chlorophenyl)-2-(2,6-difluoro-4-methoxy-phenyl)acrylonitrile (14):
    K2CO3 (2.42 g, 17 mmol) was added to a solution of (2,4,6-trifluorophenyl)-acetonitrile (2.5 g, 14 mmol) and 4-chlorobenzaldehyde (2.0 g, 14 mmol) in MeOH (30 mL). The reaction mixture was heated to reflux for 16 h, cooled, poured into H2O and filtered. The solid was washed twice with H2O and twice with heptane, and dried under vacuum to obtain 14 (1.28 g, 4.2 mmol, 30%). 1H NMR (CDCl3): δ = 3.84 (s, 3 H), 6.55 (d, J = 9.15 Hz, 2 H), 7.22 (s, 1 H), 7.43 (d, J = 8.51 Hz, 2 H), 7.82 (d, J = 8.74 Hz, 2 H). LC-MS: 1.69, 305 [M+], 307 [M++2]. 5-(4-Chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazol-3-ylamine (16): Et3N (0.16 g, 1.6 mmol) and methylhydrazine (0.75 g, 16 mmol) were added consecutively to a solution of 14 (0.5 g, 1.6 mmol) in MeOH (10 mL). The reaction mixture was heated to reflux for 72 h, then cooled and concentrated under reduced pressure to obtain 15 (0.44 g, 1.3 mmol), which was dissolved in CHCl3 (10 mL). MnO2 (1.1 g, 13 mmol) was added and the reaction mixture was stirred for 2 h at r.t., then diluted with EtOAc and filtered over Celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc–cyclohexane, 3:2), to deliver 16 (0.12 g, 0.35 mmol, 22% from 14). 1H NMR (CDCl3): δ = 3.69 (s, 3 H), 3.77 (s, 3 H), 6.41 (d, J = 9.08 Hz, 2 H), 7.15 (d, J = 8.9 Hz, 2 H), 7.33 (d, J = 8.45 Hz, 2 H). LC-MS: R t = 1.84 min; MS: m/z = 350 [M]+, 352 [M + 2]+. 3-Chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole (2): Compound 16 (60 mg, 0.17 mmol) was dissolved in concd HCl (0.5 mL) and cooled to 0 °C. A solution of NaNO2 (12 mg, 0.17 mmol) in H2O (0.1 mL) was then added dropwise. A solution of CuCl (17 mg, 0.17 mmol) in concd HCl (0.3 mL) was added and the reaction mixture was heated to 60 °C for 30 min, then the reaction mixture was neutralized by the addition of NaOH and diluted with EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc–hexane, 1:9), to deliver 2 (32 mg, 0.08 mmol, 51%).