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Volumn 73, Issue 9, 2008, Pages 3523-3529

Improved regioselectivity in pyrazole formation through the use of fluorinated alcohols as solvents: Synthesis and biological activity of fluorinated tebufenpyrad analogs

Author keywords

[No Author keywords available]

Indexed keywords

BIOACTIVITY; FLUORINATION; REGIOSELECTIVITY; SYNTHESIS (CHEMICAL);

EID: 43449106481     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo800251g     Document Type: Article
Times cited : (195)

References (52)
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    • (2003) Agrochem. Jpn , vol.83 , pp. 17-19
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    • Murakami, H.: Masuzawa, S.; Takii, S.; Ito, T. Jpn. Patent 2,012,802,003, 2003.
    • Murakami, H.: Masuzawa, S.; Takii, S.; Ito, T. Jpn. Patent 2,012,802,003, 2003.
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    • See Supporting Information for details on the preparation of compounds 1b-d
    • See Supporting Information for details on the preparation of compounds 1b-d.
  • 26
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    • Katritzky, A. R, Rees, C. W, Scriven, E. F. V, Eds. Pergamon Press: New York
    • Elguero, J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. Pergamon Press: New York, 1996; Vol. 3, pp 58-61.
    • (1996) Comprehensive Heterocyclic Chemistry II , vol.3 , pp. 58-61
    • Elguero, J.1
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    • For example, ethyl 2,4-dioxopentanoate or ethyl 2,4-dioxo-4- phenylbutanoate reacted with methylhydrazine in boiling EtOH to yield a 2:1 mixture of the two regioisomeric pyrazoles. See: Schmidt, A.; Habeck, T.; Kindermann, M. K.; Nieger, M. J. Org. Chem. 2003, 68, 5977-5982.
    • For example, ethyl 2,4-dioxopentanoate or ethyl 2,4-dioxo-4- phenylbutanoate reacted with methylhydrazine in boiling EtOH to yield a 2:1 mixture of the two regioisomeric pyrazoles. See: Schmidt, A.; Habeck, T.; Kindermann, M. K.; Nieger, M. J. Org. Chem. 2003, 68, 5977-5982.
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    • In contrast, reaction between 4-(2-thienyl)-1,1,1-trifluoromethyl-1,3- butanedione and methylhydrazine in EtOH-AcOH (10:1) at reflux afforded 1-methyl-3-trifluoromethyl-5-(2-thienyl)pyrazole in 60% yield (no presence of the other regioisomer was indicated). See: (a) Yonetoku, Y.; Kubota, H.; Okamoto, Y.; Toyoshima, A.; Funatsu, M.; Ishikawa, J.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2006, 14, 4750-4760.
    • In contrast, reaction between 4-(2-thienyl)-1,1,1-trifluoromethyl-1,3- butanedione and methylhydrazine in EtOH-AcOH (10:1) at reflux afforded 1-methyl-3-trifluoromethyl-5-(2-thienyl)pyrazole in 60% yield (no presence of the other regioisomer was indicated). See: (a) Yonetoku, Y.; Kubota, H.; Okamoto, Y.; Toyoshima, A.; Funatsu, M.; Ishikawa, J.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2006, 14, 4750-4760.
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    • 5-Hydroxy-5-trifluoromethylpyrazoline derivatives have been previously isolated and identified as intermediates in reactions between non-alkylated hydrazines and trifluoromethyl 1,3-diketones. See: (a) Elguero, J.; Yranzo, G. I. J. Chem. Res., Synopses 1990, 120-121, and references 18a-g.
    • 5-Hydroxy-5-trifluoromethylpyrazoline derivatives have been previously isolated and identified as intermediates in reactions between non-alkylated hydrazines and trifluoromethyl 1,3-diketones. See: (a) Elguero, J.; Yranzo, G. I. J. Chem. Res., Synopses 1990, 120-121, and references 18a-g.
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    • 3. See: (b) Khudina, O. G.; Shchegol'kov, E. V.; Burgart, Y. V.; Kodess, M. I.; Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Dyachenko, O. A.; Saloutin, V. I.; Chupakhin, O. N. J. Fluorine Chem. 2005, 126, 1230-1238.
    • 3. See: (b) Khudina, O. G.; Shchegol'kov, E. V.; Burgart, Y. V.; Kodess, M. I.; Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Dyachenko, O. A.; Saloutin, V. I.; Chupakhin, O. N. J. Fluorine Chem. 2005, 126, 1230-1238.
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    • A possible alternative to the general method for the synthesis of N-methylpyrazoles entails the preparation of the N-unsubstituted pyrazole, followed by methylation with methyl iodide or dimethyl sulphate under basic conditions. See: Hamper, B. C.; Leschinsky, K. L.; Mischke, D. A.; Prosch, S. D. In Asymmetric Fluoroorganic Chemistry. Synthesis, Applications and Future Directions; ACS Symposium Series 746; Ramachandran, P. V., Ed.; American Chemical Society: Washington, D.C., 2000; pp 274-275.
    • A possible alternative to the general method for the synthesis of N-methylpyrazoles entails the preparation of the N-unsubstituted pyrazole, followed by methylation with methyl iodide or dimethyl sulphate under basic conditions. See: Hamper, B. C.; Leschinsky, K. L.; Mischke, D. A.; Prosch, S. D. In Asymmetric Fluoroorganic Chemistry. Synthesis, Applications and Future Directions; ACS Symposium Series 746; Ramachandran, P. V., Ed.; American Chemical Society: Washington, D.C., 2000; pp 274-275.
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    • For a recent paper, see: (b) Dubrovina, N. V.; Shuklov, I. A.; Birkholz, M.-N.; Michalik, D.; Paciello, R.; Börner, A. Adv. Synth. Catal. 2007, 349, 21832187.
    • For a recent paper, see: (b) Dubrovina, N. V.; Shuklov, I. A.; Birkholz, M.-N.; Michalik, D.; Paciello, R.; Börner, A. Adv. Synth. Catal. 2007, 349, 21832187.
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    • Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039-3042. See also refs18b-e, g.
    • (b) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039-3042. See also refs18b-e, g.
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    • These authors proposed a mechanism with a sequential loss of two water molecules that could explain the observed high regioselectivity. The first loss of water would be fast, corresponding to the formation of the C=N bond conjugated with the aryl ring, whereas the second loss of water would be much slower, even requiring acid catalysis for the elimination to proceed. See ref 18g
    • These authors proposed a mechanism with a sequential loss of two water molecules that could explain the observed high regioselectivity. The first loss of water would be fast, corresponding to the formation of the C=N bond conjugated with the aryl ring, whereas the second loss of water would be much slower, even requiring acid catalysis for the elimination to proceed. See ref 18g.
  • 49
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    • An alternative mechanism would involve addition to the carbonyl attached to the RF group followed by a second addition to the other carbonyl to form a 3,5-dihydroxypyrazoline, which would then evolve to the corresponding pyrazole through sequential double dehydration. See ref 20a
    • F group followed by a second addition to the other carbonyl to form a 3,5-dihydroxypyrazoline, which would then evolve to the corresponding pyrazole through sequential double dehydration. See ref 20a.
  • 52
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    • Masai is commercialized by BASF
    • Masai is commercialized by BASF.


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