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    Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

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        Abstract

        The activation of aromatic diaryl isoxazoles with strong electron-withdrawing groups, such as the nitro, triflyl, and the phenylsulfonyl groups, at the 4-position has enabled the first regio- and diastereoselective difluoromethylation at the 5-position of isoxazoles by nucleophilic addition using (difluoromethyl) trimethylsilane, Me3SiCF2H, to provide difluoromethylated isoxazolines in good yields. Conjugated styryl-4-nitroisoxazoles were also nicely converted into the corresponding CF2H adducts with high regio- and excellent diastereoselectivities. Since the trifluoromethylated analogs of the corresponding diaryl-isoxazolines are effective ectoparasiticides, represented by fluralaner, should a series of difluoromethylated isoxazolines be obtained, they would be of great importance as promising drug candidates in this field.

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        Most cited references 45

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        Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

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          Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments

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            Tetrahedron report number 221

             John Welch (1987)
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              Author and article information

              Affiliations
              [1 ]Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan
              [2 ]Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan
              Author notes
              [* ]Corresponding author's e-mail address: nozshiba@ 123456nitech.ac.jp

              Dedication: To Professor Iwao Ojima for his 70th birthday.

              Contributors
              (View ORCID Profile)
              Journal
              SOR-CHEM
              ScienceOpen Research
              ScienceOpen
              2199-1006
              18 December 2014
              : 0 (ID: aeab23b4-61ff-4936-a252-0cd98d9fddcf )
              : 0
              : 1-7
              2683:XE
              10.14293/S2199-1006.1.SOR-CHEM.AD1QVW.v2
              © 2014 Xin Wang et al.

              This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

              Counts
              Figures: 6, Tables: 3, References: 67, Pages: 7
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              Original article

              Comments

              wrote:

              As mentioned by the authors, the difluoromethyl (CF2H) group is generally regarded as isosterer to a hydroxy (OH) and thiol (SH). However, the power of the difluoromethyl group is not well-understood because of lacking the general method for the introduction of the difluoromethyl group. The authors studied the factors that might affect the reaction of TMSCF2H with substituted isoxazoline-a medicinally important structure unit. As a result, the best reaction conditions were identified and a variety of substituted difluoromethylated isoxazolines were generated. The control of the diastereoselectivity is intriguing but nicely controlled for the vinyl substituted isoxazoline derivatives. Nice work.

              The study of the bioactivity of these compounds would be expected in the following investigation.

              2015-05-24 02:48 UTC
              +1

              Dear Qilong,

              Thank you very much for your kind comments on paper, and I agree with your comments that the potential of CF2H is not simple and great. More systmmatic biological studies on CF2H-compounds should be required and we also work on this line using our compounds.

              Best wishes,

              Norio

              2015-05-24 02:59 UTC
              Dear Professor Dmitry Katayev, Thank you very much for your strong support on our article. The CF2H-analoges of Bravecto is of very attractive, however, due to a lack of general synthetic methods, the research has less been examined. Our method for the preparation of CF2H-analoges by the direct difluoromethylation has a wide substrate generality. We hope the research of CF2H-analoges of Bravecto will be more activated. Incidentally, your contribution to this review is of great helpful not only for our paper but also for ScienceOpen, since the ScienceOpen has a very unique reviewing system which could change the style of reviewing in future. Norio
              2015-03-31 11:02 UTC
              +1
              wrote:
              Comments The authors reported a new method for the preparation of 5-difluoromethyl-2-isoxazoline derivatives through direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using TMSCF2H. Although this is an extension of their previous work and the yields of difluoromethylated products are moderate, the manuscript still can be published in ScienceOpen because of the difficulty in nucleophilic difluormethylation of aromatic isoxazoles. In addition, the resulting new 5-difluoromethyl-2-isoxazoline derivatives may have potential applications in agrochemicals. If the authors could stereoselectively synthesize compounds 2 and 4, it will improve the quality of the manuscript. Level of importance: 3 Is the publication of relevance for the academic community and does it provide important insights? Yes Does the work represent a new approach or new findings in comparison with other publications in the field? Yes Level of validity:4 Is the hypothesis clearly formulated? Yes Is the argumentation stringent? Yes Are the data sound, well-controlled and statistically significant? Yes Is the interpretation balanced and supported by the data? Yes Are appropriate and state-of-the-art methods used? Yes Level of completeness: 4 Do the authors reference the appropriate scholarly context? Yes Do the authors provide or cite all information to follow their findings or argumentation? Yes Do they cite the all relevant publications in the field? Yes Level of comprehensibility: 4 Is the language correct and easy to understand for an academic in the field? Yes Are the figures well displayed and captions properly described? Yes Is the article systematically and logically organized? Yes
              2015-03-19 11:52 UTC
              +1
              wrote:
              Comments The authors reported a new method for the preparation of 5-difluoromethyl-2-isoxazoline derivatives through direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using TMSCF2H. Although this is an extension of their previous work and the yields of difluoromethylated products are moderate, the manuscript still can be published in ScienceOpen because of the difficulty in nucleophilic difluormethylation of aromatic isoxazoles. In addition, the resulting new 5-difluoromethyl-2-isoxazoline derivatives may have potential applications in agrochemicals. If the authors could stereoselectively synthesize compounds 2 and 4, it will improve the quality of the manuscript. Level of importance: 3 Is the publication of relevance for the academic community and does it provide important insights? Yes Does the work represent a new approach or new findings in comparison with other publications in the field? Yes Level of validity:4 Is the hypothesis clearly formulated? Yes Is the argumentation stringent? Yes Are the data sound, well-controlled and statistically significant? Yes Is the interpretation balanced and supported by the data? Yes Are appropriate and state-of-the-art methods used? Yes Level of completeness: 4 Do the authors reference the appropriate scholarly context? Yes Do the authors provide or cite all information to follow their findings or argumentation? Yes Do they cite the all relevant publications in the field? Yes Level of comprehensibility: 4 Is the language correct and easy to understand for an academic in the field? Yes Are the figures well displayed and captions properly described? Yes Is the article systematically and logically organized? Yes
              2015-03-19 11:52 UTC
              +1
              Dear Professor 新刚 张, Thank you very much for your strong support on our manuscript. The yields of this transformation are moderate around 50% and the trifluoromethylation variant proceeds more easily. This is due to the difference of bond order between CF3-Si and CF2H-Si. The diastereoselectivities for 2 and 4 are high up to 100%, and enantioselective diifluoromethylation is the next challenge. Biological application of the series of these compounds will be examined in near future. Thank you very much one again for your positive support on our article. Best wishes, Norio
              2015-03-19 11:45 UTC
              +1
              A useful synthetic method of organofluorine compounds is described. Difluoromethylation of organic compounds is one of the challenging topics in organic chemistry. Even now, there have been the limited examples of difluoromethylation due to the difficulty. The authors have succeeded in nucleophilic difluoromethylation of aromatic isoxazoles bearing electron-withdrawing groups. The findings in this paper are of basic interest and the products are useful in several fields of science. Therefore, I support publication in ScienceOpen. Some corrections in the manuscript would be needed. (a) Page 1, line 10; [39–40, 41] -> [39–41] (b) Page 2, left, line 20; were believed to be useless -> were believed to be not very useful (‘useless’ is too strong, because there has been little knowledge about the reactivity of HCF2SiMe3 in detail until Hu’s report.) (c) Page 7, authors’ names in ref-44 and 45; all the first names and family names are incorrect.
              2015-03-09 13:14 UTC
              +1
              One person recommends this
              Dear Professor Amii, Thank you very much for your comments on our paper. I am so happy to receive your positive comments. The paper will be revised soon according to your suggestions. The journal, ScienceOpen, has a new style of revising system, and it is very challenging. We hope this journal should be sucsess. Best wishes, Norio .
              2015-03-09 13:46 UTC
              Dear Professor Luke Hunter, Thank you very much for your positive comments on our manuscript. I had been waiting for a very long time to get the first comment, since submission. This reviewing system should be improved to get success of ScienceOpen. The present our manuscript will be revised soon, based on your comments. Thank you very much once again for your support on our paper. Best wishes, Norio
              2015-03-07 23:12 UTC
              +1

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