Unique Properties of Fluorine and their Relevance to Medicinal Chemistry and Chemical Biology

Yamazaki, Takashi; Taguchi, Takeo; Ojima, Iwao

doi:10.1002/9781444312096.ch1

Cited by 156 publications

(230 citation statements)

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“…[1,2] Due to its metabolic stability, lipophilicity, and electron-withdrawing character, [3] use of the trifluoromethyl (CF 3 ) substituent has gained considerable attention in recent years. New methods for direct C-CF 3 bond-formation have had a prominent presence in current literature, highlighting the importance of this transformation.…”

Section: Abstract Trifluoromethylation; Fluorine; Iron; Catalysismentioning

confidence: 99%

Iron(II)‐Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates

2012

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An iron(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates has been developed. The reactions proceed under mild conditions and provide E/Z selectivities of > 95:5 for 2-aryl and -heteroarylvinyl substrates. Experimental observations suggest that the reaction does not proceed through a transmetallation of the RBF 3 K to the iron catalyst. Keywords trifluoromethylation; fluorine; iron; catalysisThe incorporation of fluorinated functional groups in pharmaceutical and agrochemical molecules has had a significant impact on the discovery and development of biologically active compounds. [1,2] Due to its metabolic stability, lipophilicity, and electron-withdrawing character, [3] use of the trifluoromethyl (CF 3 ) substituent has gained considerable attention in recent years. New methods for direct C-CF 3 bond-formation have had a prominent presence in current literature, highlighting the importance of this transformation. [4,5] Efforts in our lab have focused on the development of new fluorination [6] and trifluoromethylation [7] reactions through the use of transition metal catalysis and promotion. Herein, we report a facile method to access vinyl-CF 3 functional groups through an iron(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates (1) using Togni's reagent 2 [8] (eq 1).Recently, we reported an oxidative trifluoromethylation of terminal olefins, providing rapid access to allyl-CF 3 containing products of type 4. [9,10] During the course of our studies, we observed 5, a side product resulting from chloride counterion transfer from CuCl to the olefin substrate subsequent to C-CF 3 bond formation (Figure 1, A). We hypothesized several possible intermediates (summarized as 6) leading to the formation of both 4 and 5. [*] Fax: (+1) 617-253-329 sbuchwal@mit.edu. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. After consideration of these possibilities, we surmised that regioisomeric products (i.e. vinyl-CF 3 containing molecules) might be accessed through a similar type of reactive intermediate. Toward this end, we sought to bias the presumed product-forming step through the use of a functionalized vinyl substrate such as a vinylboron reagent (Figure 1, B). Thus, trifluoromethylation of 7 would lead to formation of intermediate 6d. Loss of the boronbased functional group would result in the generation of the desired vinyl-CF 3 containing product. NIH Public AccessWe commenced our studies by examining the trifluoromethylation of styryl-BX n reagents with 2 using various metal catalysts. During our preliminary studies, we discovered that both copper(I) [11] and iron(II) chloride provided a satisfactory yield of product 3a (Table 1, entries 1-4). Due to the low cost and cleaner reaction profile, we continued our studies using catalytic FeCl 2 by examining various vinylboron reagents (Table 1, entries 2-4). Interestingly, the E/Z product ratio varied significantly depending on the identity of styryl-BX n r...

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Section: Abstract Trifluoromethylation; Fluorine; Iron; Catalysismentioning

confidence: 99%

Iron(II)‐Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates

2012

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“…We hypothesized that this transformation might be achieved using a Cu-based strategy involving the generation of an allylic radical and a subsequent CF 3 • transfer [Scheme 1, Path A]. [18] Alternatively, if reagent 1 could be used as an electrophilic CF 3 • equivalent, 2 may be generated via an atom transfer radical addition (ATRA)-type pathway (Path B). [19] Finally, an electrophilic trifluoromethylation proceeding through a cationic intermediate may also be viable (Path C).…”

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confidence: 99%

Copper‐Catalyzed Trifluoromethylation of Unactivated Olefins

2011

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“…The introduction of fluorine or appropriate fluorinated functions into a molecule has become an invaluable tool for medicinal chemists 1,2 . Substitution of fluorine into a potential drug molecule not only alters the electronic environment, but it also influences the properties of neighboring functional groups.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of fluoropyrazolesulfonylurea and thiourea derivatives as possible antidiabetic agents

Faidallah

Al-Mohammadi

Alamry

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Fluorinated pyrazoles, benzenesulfonylurea and thiourea and their cyclic sulfonylthiourea derivatives were prepared as hypoglycemic agents. The chemistry involves the condensation of 4-hydrazino benzenesulfonamide hydrochloride with fluorochalcones to give pyrazoline derivatives which upon oxidation with bromine water afforded corresponding pyrazoles. Reaction of pyrazolines with isocyanates and isothiocyanates give the corresponding ureas and thioureas. Subsequent cyclization of these thiourea derivatives with ethyl bromoacetate and a-bromoacetophenone yielded the 4-oxothiazolidines and thiazolines, respectively. Preliminary biological screening of the prepared compounds revealed significant antidiabetic activity. Molecular and biological properties calculations revealed favorable drug-like profiles of six compounds. The structure-activity relationship (SAR) and in silico drug relevant properties calculations (HBD, HBA, tPSA, miLogP, molecular weight, % ABS, drug-likeness and drug score) endorse that these compounds are potential leads for future drug discovery study.

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Unique Properties of Fluorine and their Relevance to Medicinal Chemistry and Chemical Biology

Cited by 156 publications

References 0 publications

Iron(II)‐Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates

Iron(II)‐Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates

Copper‐Catalyzed Trifluoromethylation of Unactivated Olefins

Synthesis and biological evaluation of fluoropyrazolesulfonylurea and thiourea derivatives as possible antidiabetic agents

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