Chemo- and Stereoselective Synthesis of Fluorinated Enamides from Ynamides in HF/Pyridine: Second-Generation Approach to Potent Ureas Bioisosteres

Abstract

(E)- and (Z)-α-fluoroenamides could be easily prepared with high levels of chemo- and regioselectivities by hydrofluorination of readily available ynamides with HF/pyridine. The scope and limitations of this new process for the hydrofluorination of ynamides, as well as the stability of the resulting α-fluoroenamides, have been extensively studied. Theoretical calculations at the MP2 and B3LYP levels of theory showed that the resulting fluoroenamides exhibit geometrical and electronic properties that partially mirror those of ureas, therefore demonstrating that the hydrofluorination of ynamides provides a general, straightforward, and user-friendly approach to bioisosteres of ureas, potent building blocks for biological studies and medicinal chemistry.

Copper-Catalyzed Tandem Decyclization-Cyclization Reaction of N-Alkynyl-3-hydroxyisoindolin-1-ones Generated from N-Alkynyl Phthalimides: Selective Synthesis of ortho-(2-Oxazolyl)phenyl Ketones

“…1 and 2). 3 The α-regioselective addition of heteronucleophiles to the alkynyl group was also observed for the various Lewis acid-catalyzed reactions of ynamides 1, 2 which is most probably due to the sufficient electron donation from nitrogen to the neighboring alkynyl group. In contrast, we found that the reaction of N-alkynyl phthalimides 4 with alcohols can lead to ortho-(2-oxazolyl)benzoates 6 and β-ketoimides 7 (Scheme 1, eq.…”

“…4,5 The reaction is extremely sensitive to the Lewis acid character. The use of σ-electrophilic Lewis acids, such as CeCl 3 and MgCl 2 , gave oxazoles 6, and increasing the π-electrophilic Lewis acidity tended to decrease the yields of the oxazole 6 and increase the production of β-ketoimides 7. We speculated that N-alkynyl-3-alkoxy-3-hydroxyisoindolin-1-one 5 generated from the nucleophilic addition of an alcohol to imide carbonyl is a common intermediate involved in these types of transformations, although direct attempts to identify intermediate 5 were not successful.…”

(Radio)fluoroclick Reaction Enabled by a Hydrogen‐Bonding Cluster

“…[17] Keteniminium A possesses a linear geometry, [17] with its upper face being sterically hindered by the R 1 group, thus favoring the nucleophile (fluoride) syn approach (formation of the syn -addition product) (Scheme 3., top). [18] On the other hand, in the presence of NIS, an iododium B forms instead because NIS is a strong electrophile; ring-opening of B by fluoride yields the anti -addition product 3 (Scheme 3., bottom).…”

“…[11] Because HFIP is as tronger Hbond donor than those alcohols,w ee xpected it to have an even stronger effect in the modulation of the nucleophilicity of fluoride.F inally,aH-bond network generated from HFIP could also act as ap roton source in hydrofluorination (Scheme 1c), as shown by Doyle and co-workers in their copper-catalyzed HÀFi nsertion into a-diazocarbonyl compounds with HFIP as the proton source. [12] We are now glad to report the first protocol for 18 Faddition to an alkyne through anucleophilic (radio)fluoroclick reaction, enabled by ahydrogen-bonding cluster and using readily available KF( 18 F) (Scheme 1d).…”

“…Ynamides are readily available compounds that have found wide application in organic synthesis. [13] Although the hydrofluorination of ynamides has been reported, [14] these methods are based on hydrogen fluoride or silver fluoride as the fluorination reagent, both of which are not environmentally friendly.More importantly,the introduction of 18 Fisd ifficult by these methods.I nitially,w e chose HFIP as our hydrogen-bonding activator and proton source.S creening of various alkali metal fluorides indicated that metal fluorides with bulkier counterions gave better results ( Having found the optimal conditions,w et hen explored the scope and functional-group tolerance of our hydrofluorination protocol (Table 2). First, we evaluated the effect of R 2 substitution in ynamides 1 ( Table 2).…”