Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives

Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives

Klaus Albertshofer* and Neelakandha S. Mani
Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States

 DOI: 10.1021/acs.joc.5b02592
J. Org. Chem.

Abstract:
 

We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorina- tion with N-fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6-tetramethylpiperidine. Aided by a controlled protecting group switch, we were able to effectively target both the reactive 5- as well as the difficult to target 4-position of these molecules, leading to a series of fluorinated polysubstituted imidazoles in gram scale.

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Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination

Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination

Sydonie D. Schimler,† Sarah J. Ryan,† Douglas C. Bland,‡ John E. Anderson,‡ and Melanie S. Sanford*,†

† Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States ‡ Process Science, Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States

J. Org. Chem. DOI: 10.1021/acs.joc.5b02075
http://pubs.acs.org/doi/pdf/10.1021/acs.joc.5b02075

Abstract:

This paper describes the room-temperature SNAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more costeffective than fluorination with CsF.

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Hypervalent Iodine-Mediated Fluorination of Styrene Derivatives: Stoichiometric and Catalytic Transformation to 2,2- Difluoroethylarenes

Hypervalent Iodine-Mediated Fluorination of Styrene Derivatives: Stoichiometric and Catalytic Transformation to 2,2- Difluoroethylarenes

Tsugio Kitamura,* Kensuke Muta, and Juzo Oyamada Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering, Saga University, Hojo-machi, Saga 840-8502, Japan

Journal of Organic Chemistry    http://pubs.acs.org/doi/pdf/10.1021/acs.joc.5b01929

Abstract:
Fluorination of styrene derivatives with a reagent system composed of μ-oxo-bis[trifluoroacetato(phenyl)iodine] and a pyridine·HF complex gave the corresponding (2,2-difluoroethyl)arenes in good yields. Similarly, the reagent of PhI(OCOCF3)2 and the pyridine·HF complex acted as a fluorinating agent for styrene derivatives. The fluorination of styrene derivatives with the pyridine· HF complex underwent under catalytic conditions using 4-iodotoluene as a catalyst and m-CPBA as a terminal oxidant.

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