Abstract:Herein, conditions are provided for the formation and use of the oxazolone enolate for the nucleophilic substitution of highly fluorinated (hetero) arenes, which after unmasking yield highly fluorinated non-natural amino acids and derivatives. In addition, the properties and chemical behavior of this new class of amino acids are explored. The utility is demonstrated in the one pot synthesis of medicinally relevant 2-aminohydantoins.
“…A side-view of a cross section of the electron density surface (through C1 and C4 perpendicular to the molecular plane) indicates that attack of the nucleophile at C1 may be somewhat occluded by the attached chlorine approaching at the Bürgi–Dunitz angle, 46 (Figure 4B). Curiously, this is in contrast to our previous observation, 41 in which the addition of an oxazolone enolate to 4-chlorotetrafluoropyridine gave substitution at the 4 position as the major product, which is the same as the fluorinated analog. Of all the factors discussed, they all seem to support the observed selectivity of the reaction, however, the relative contribution of each is still unclear.…”
Functionalized per- and poly-fluoroarenes are important building blocks, with many industrially and medicinally important molecules containing them. Nucleophilic aromatic substitution can be employed as a quick and straightforward way to synthesize these building blocks. While many methods to derivatize fluoroarenes exist which use heteroatom centered nucleophiles, there are fewer methods that use carbon centered nucleophiles, and of those many are poorly defined. This work presents the SNAr reaction of nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition was probed using both DFT calculations and experimentally via halogen exchange.
“…A side-view of a cross section of the electron density surface (through C1 and C4 perpendicular to the molecular plane) indicates that attack of the nucleophile at C1 may be somewhat occluded by the attached chlorine approaching at the Bürgi–Dunitz angle, 46 (Figure 4B). Curiously, this is in contrast to our previous observation, 41 in which the addition of an oxazolone enolate to 4-chlorotetrafluoropyridine gave substitution at the 4 position as the major product, which is the same as the fluorinated analog. Of all the factors discussed, they all seem to support the observed selectivity of the reaction, however, the relative contribution of each is still unclear.…”
Functionalized per- and poly-fluoroarenes are important building blocks, with many industrially and medicinally important molecules containing them. Nucleophilic aromatic substitution can be employed as a quick and straightforward way to synthesize these building blocks. While many methods to derivatize fluoroarenes exist which use heteroatom centered nucleophiles, there are fewer methods that use carbon centered nucleophiles, and of those many are poorly defined. This work presents the SNAr reaction of nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition was probed using both DFT calculations and experimentally via halogen exchange.
“…We expanded our study of substrates which involved 6-membered hydrogen bonds by exploring non-natural alpha amino acids derivatives (Scheme 9), which are rapidly synthesized via perfluoroarylation of the oxazolone followed by the appropriate workup, 38 or in the case of 9d via the addition of nitromethane followed by hydrogenation. 39 We were pleased to see that the benzoyl protected amino acids ( 9a and 9b ) underwent smooth photo-HDF, and that the HDF products were isolated in good yields.…”
The photocatalytic C–F functionalization of highly fluorinated arenes is a powerful method for accessing functionalized multifluorinated arenes. The decisive step in the determining regioselectivity in fluorine functionalization is fluoride fragmentation from the radical anion of the multifluorinated arene. To date, the availability of regioisomers has been dictated by the innate electronics of the fluorinated arene, limiting the synthetic utility of the chemistry. This study investigates the remarkable ability of a strategically located hydrogen bond to transcend the normal regioselectivity of the C–F functionalization event. A significant rate acceleration is additionally observed for hydrodefluorination of fluorines that can undergo intramolecular hydrogen bonds that form 5–8 membered cycles with moderately acidic N–Hs. The hydrogen bond is expected to facilitate the fragmentation not only by bending the C–F bond of the radical anion out of planarity, but also by increasing the exothermicity of the fluoride extrusion step through protonation of the naked fluoride. Finally, the synthetic utility of the method is demonstrated in an expedited synthesis of the trifluorinated α-phenyl acetic acid derivative required for the commercial synthesis of Januvia, an anti-diabetic drug. This represents the first synthesis of a commercially important multifluorinated arene via a defluorination strategy, and is significantly shorter than the current strategy.
“…Another method for the incorporation of perfluoroaromatic residues into amino acids was reported by Weaver and co-workers ( Scheme 15 ) [ 74 ]. In this report, a series of perfluoroaromatic groups was added directly to the α carbon, removing the need for an existing nucleophilic group.…”
“…It was also found that fully substituted amino acids could also be furnished using this synthetic approach. Scheme 15 Synthesis of perfluoro-amino acids, Weaver and co-workers [ 74 ]. …”
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
