Regio- and Stereoselective Addition to gem-Difluorinated Ene–Ynamides: Access to Stereodefined Fluorinated Dienes

Abstract

The first synthesis of gem-difluorinated ene-ynamides is presented via deprotonation of trifluoromethylated Nallenamides and extrusion of fluorine. These highly reactive building blocks, owing to their dual functional groups, offer a unique entry to difluorinated dienes and to stereodefined, monofluoro-substituted dienes. Stereoselective addition to the ynamide moiety led to difluorinated dienes. A stereocontrolled domino  elimination reaction followed by an addition/elimination sequence from trifluoromethylated N-allenamides provided exclusively stereodefined monofluorinated ene-ynamides. ASSOCIATED CONTENTSupporting Information. The Supporting Information is available free of charge on the ACS Publications website. General methods, synthetic procedures, characterization data and copies of 1 H, 13 C and 19 F NMR spectra and X-ray crystallography data.CCDC 2164358 and 2155397 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk

Construction of C–N and C–O bonds based on N-allenamide functionalization

“…Recently, we reported an α deprotonation of trifluoromethylated N -allenamides 171 followed by a γ-elimination of fluoride offering an entry to a new class of ynamides: difluorinated ene-ynamides 172 . 50 An S N V reaction occurred when difluorinated ene-ynamides were treated with alcoholates leading to difluorinated N -allenamides substituted with a methoxy group at the γ-position (R = Me) 175 or to mono-fluorinated ene-ynamides 174 when (R ≠ Me) (Scheme 42).…”

Silver-Catalyzed Domino Reaction of CF3-Substituted N-Allenamides with Primary Amines for the Construction of 2-Amido-5-fluoropyrroles

“…To support our idea, we subjected gem -difluorinated ene-ynamide 2a to the addition of benzylamine in the presence of silver bistriflimide (AgNTf 2 ) to activate the ynamide moiety according to our previous observations . Surprisingly, we obtained directly the corresponding 2-amido-5-fluoropyrrole 3a in 37% yield.…”

“…In view of the limited approaches for the incorporation of fluorine on pyrroles and our interest in ynamide chemistry, we envisioned that gem -difluorinated ene-ynamides could be employed to generate fluorinated pyrroles via hydroamination followed by cyclization.…”

“…Based on our experimental findings, we postulate the following mechanism. The reaction starts with the deprotonation of trifluoromethylated N -allenamides and the δ extrusion of fluoride, providing gem -difluorinated ene -ynamides 2 . Notably, when benzylamine and isopropanol were simultaneously added to CF 3 -substituted N -allenamide 1a , the monofluorinated ene -ynamide where isopropylate was added to the gem -difluorinated moiety was obtained exclusively in 95% yield, thus discriminating the addition of the primary amine on the difluoroalkene moiety.…”

“…β-Elimination of AgF delivers the 2-amido-5-fluoropyrroles 3 . When amino phenols are employed, addition of the phenolate to the difluorinated alkene moiety resulted in the formation of monofluorinated ene -ynamide substituted with an alkoxy group 5 . Hydroamination of the ynamide moiety provides the eight-membered benzoxazole F .…”