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

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.

Automated summary

Electrochemical access to organometallic redox reagents allows for selective synthesis of various benzene derivatives with different regioisomers. A unified electrochemical strategy is presented for the selective cyclotrimerization of terminal alkynes to access both 1,3,5- and 1,2,4-regioisomeric trisubstituted benzene derivatives. The regiocontrol can be switched by the addition of a carboxylic acid.