Catalytic Hydrodifluoroalkylation of Unactivated Olefins
Wen-Jun Yue, Craig S. Day, Adrian J. Brenes Rucinski and Ruben Martin*
*Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain,
Email: rmartinromo
iciq.es
W.-J. Yue, C. S. Day, A. J. B. Rucisnski, R. Martin, Org. Lett., 2022, 24, 5109-5114.
DOI: 10.1021/acs.orglett.2c01941
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Abstract
A cooperative interplay of halogen- and hydrogen-atom transfer enables the synthesis of gem-difluoroalkanes from unactivated sp3 precursors. The method is characterized by its simplicity, generality, and site selectivity, including the functionalization of advanced intermediates and olefin feedstocks.
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proposed mechanism
4CzIPN
Details
The document discusses a new catalytic technique for the hydrodifluoroalkylation of unactivated olefins, enabling the preparation of gem-difluoroalkanes from simple sp3 precursors. This method is notable for its simplicity, generality, and site selectivity, making it valuable for drug discovery. The approach leverages a cooperative interplay of halogen- and hydrogen-atom transfer, avoiding the need for harsh conditions or stoichiometric organometallic reagents. The study found that using a combination of 4-CzIPN, AdSH, and DIPEA in MeCN/H2O under blue-LED irradiation yielded high amounts of the desired product. The method showed good functional group tolerance and was effective with various substrates, including those containing alcohols, carboxylic acids, ketones, amides, and more. The technique also worked well with light olefin feedstocks like ethylene, propene, and butene. Preliminary mechanistic experiments supported the proposed mechanism involving halogen-atom transfer and hydrogen-atom transfer. The study concludes that this catalytic strategy offers a reliable and rapid way to access a broad range of alkyl difluoroalkanes, with potential immediate utility in synthesizing valuable sp3 fluorinated architectures.
Hydro-Difluoroalkylation of Unactivated Olefins
The hydro-difluoroalkylation of unactivated alkenes was performed with 451 nm LEDs (OSRAM Oslon® SSL 80 royal-blue LEDs), which were installed at the bottom of a custom-made 8 flatbottom Schlenk tubes holder, equipped with a cooling system (the temperature was set at 20 °C) and a magnetic stirrer (~ 500 rpm).
General procedure A: An oven-dried 8 mL Schlenk tube containing a stirring bar was charged with olefin (0.20 mmol, 1.0 equiv) and 4CzIPN (1.80 mg, 0.01 equiv). The tube was then introduced in the nitrogen-filled glovebox where the DIPEA (70 μL, 2.0 equiv) was added. Then, the tube was brought outside the glovebox, and difluorobromoalkane (0.40 mmol, 2.0 equiv), CH3CN (2 mL), degassed H2O (0.20 mL) and AdSH (16 μL 0.5 M solution in CH3CN, 0.04 equiv) were added to the reaction mixture sequentially under N2 atmosphere. Then, the tube was stirred at 20 °C under blue LED irradiation with a cooling system for 24 hours. At that time, the reaction was quenched by the addition of EtOAc (5 mL), and the reaction mixture was concentrated under vacuum prior to purification by flash chromatography column on silica gel.
General procedure B: An oven-dried 8 mL Schlenk tube containing a stirring bar was charged with 4CzIPN (1.80 mg, 0.01 equiv). The tube was then introduced in the nitrogen-filled glovebox where the DIPEA (70 μL, 2.0 equiv) was added. Then, the tube was brought outside the glovebox, and olefin (0.60 mmol, 3.0 equiv), difluorobromoalkane (0.20 mmol, 1.0 equiv), CH3CN (2 mL), degassed H2O (0.20 mL) and AdSH (16 μL 0.5 M solution in CH3CN, 0.04 equiv) were added to the reaction mixture sequentially under N2 atmosphere. Then, the tube was stirred at 20 °C under blue LED irradiation with a cooling system for 24 hours. At that time, the reaction was quenched by the addition of EtOAc (5 mL), and the reaction mixture was concentrated under vacuum prior to purification by flash chromatography column on silica gel.
Key Words
difluoralkanes, fluoroalkylation, photochemistry
ID: J54-Y2022
