H-bonding vs Protonation of Alkynes in Regioselective Hydroamination Reactions: A Glimpse into the Reactivity of Arylogous Ynolethers and Ynamines

Abstract

In this paper is described the competition and transition between hydrogen bonding and protonation of alkynes connected, on one side, to various aromatic rings and to chiral amino ester appendages on the other side. While the first mode of activation induced the cyclization into pyrrolidines, the protonation of the alkyne led preferentially to tetrahydropyridines due to the higher level of the highest occupied molecular orbital (HOMO) of the considered arylogous ynolethers and ynamines. The transition between H-bonding and protonation was observed with the alkyne substituted with 2-methoxyphenyl, for which the cyclization delivered either five- or six-membered rings depending on the temperature of the experiment. From there, the cyclization of dialkoxy- and trialkoxyphenyl-substituted alkynes into six-membered rings, i.e., tetrahydropyridines, was developed. When next applied to alkynylindoles, the same pattern of cyclization provided six-membered rings as an illustration of the reactivity of arylogous ynamines. Thanks to the high reactivity of the intermediate cationic species, weak nucleophiles such as NH-oxazolidinone participated efficiently in the hydroamination reaction of alkynylindoles. Pyrrolidines, tetrahydropyridines, and piperidines decorated with various aromatics and substituents were thus prepared in enantio- and stereoselective manner. Capitalizing on the enamine moiety of the azaheterocycles, the molecular diversity was extended through stereoselective oxidation and ring contraction processes.

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids

“…According to the experimental results and literature reports, a plausible mechanism for the reaction in a generalized form was proposed in Scheme . 2-Ethynylbenzoic acid 1a generates intermediate C through the protonation ( A ), cyclization ( B ), and isomerization ( C ) of the carboxylic acid (path a). Another pathway is that cyclization can occur by hydrogen bonding between the triple bond and the TfOH ( D ), which activates the alkyne toward intramolecular nucleophilic addition (path b) . Then, intermediate E , which is protonated from intermediate C , is electrophilically attacked by electron-rich aromatic rings or intermediate C to give the final products or self-polymerization product 4a .…”

“…8dg Another pathway is that cyclization can occur by hydrogen bonding between the triple bond and the TfOH (D), which activates the alkyne toward intramolecular nucleophilic addition (path b). 9 Then, intermediate E, which is protonated from intermediate C, is electrophilically attacked by electronrich aromatic rings or intermediate C to give the final products or self-polymerization product 4a.…”

Tricepyridinium‐inspired QACs yield potent antimicrobials and provide insight into QAC resistance

“…Attempts at replicating the previously‐reported synthesis of tricepyridinium bromide proved unreliable, with low yields and reproducibility; this, coupled with prohibitively high costs of starting materials led us to devise an alternate synthetic route [7] . Our improved route begins with a regioselective 3‐iodination of indole ( 2 ), followed by protection of the nitrogen atom with a tert ‐butoxycarbonyl (Boc) moiety [10] . Using the lithiation‐borylation methodology established by Watson and Aggarwal, the iodine was replaced with a pinacolborane substituent to give 4 [11] .…”