Unified Electrochemical Synthetic Strategy for [2 + 2 + 2] Cyclotrimerizations: Construction of 1,3,5- and 1,2,4-Trisubstituted Benzenes from Ni(I)-Mediated Reduction of Alkynes
Sagar Arepally, Ponnusamy Nandhakumar, Gisela A. González‐Montiel, Alina Dzhaparova, Gyeongho Kim, Ahyeon Ma, Ki Min Nam, Haesik Yang, Paul Ha‐Yeon Cheong, Jin Kyoon Park
Abstract
Electrochemical access to organometallic redox reagents can broaden the potential and impact of organic syntheses, as a selective reaction pathway could be achieved. Herein, we present a unified electrochemical synthetic strategy for the paired electrochemical [2 + 2 + 2] cyclotrimerizations of terminal alkynes to selectively access both 1,3,5- and 1,2,4-regioisomeric trisubstituted benzene derivatives. The regiocontrol in our process can be simply switched by the addition of a carboxylic acid. In the presence of an acid, 1,3,5-isomers were synthesized exclusively, whereas in the absence of acid, 1,2,4-isomers were formed predominantly. The scope of this electrochemical cyclotrimerization was surprisingly broad and mildly effective, tolerating both electron-rich and electron-poor substrates, including redox-sensitive bromide substitutions. Detailed mechanistic investigations involving cyclic voltammetry, electron paramagnetic resonance spectroscopy, deuterium exchange, and quantum mechanical computations were performed. Mechanistically, the pivot between the 1,3,5- and 1,2,4-selectivity appears to be governed by the protonation of the reduced alkyne which shifts the radical distribution from a terminal to an internal position and thus in turn dictates the regiocontrol of the subsequent radical coupling processes. The data are consistent with a mechanism where the reduction of the alkyne occurs by Ni(I) in both the 1,3,5- and 1,2,4-processes.