Theoretical Insight into the Mechansim and Origin of Ligand-Controlled Regioselectivity in Homogenous Gold-Catalyzed Intramolecular Hydroarylation of Alkynes

Abstract

This work aims at understanding the mechanism and regioselectivity in ligand-controlled gold-catalyzed divergent intramolecular hydroarylation of alkynes reported by Jiang et al. ( J. Am. Chem. Soc. 2016 , 138 , 5218 - 5221 ). Focusing on a representative alkyne, N-propargyl-N-tosylaniline, we conducted a detailed computational study on the ortho- and para-position hydroarylation of the alkyne catalyzed by gold(I) catalysts with different ligands. Both the ortho- and para-position hydroarylation reactions are found to follow a similar three-stage mechanism: electrophilic cyclization, proton loss, and protiodeauration. The initial electrophilic cyclization was identified as the rate- and regiochemistry-determining step. With the flexible electron-deficient phosphite ligand, the ortho-position cyclization is identified as the energetically more favorable pathway, while with the rigid electron-abundant phosphine (Xphos) ligand, the dominant pathway turns to the para-position cyclization. The theoretical results are in good agreement with the experimental observations. The π-π interaction between alkynyl phenyl and the directing acylamino group are found to be mainly responsible for the observed ortho-selectivity, while a combination of favorable noncovalent CH···π interaction and steric repulsion between Xphos ligand and alkynyl group contributes to the observed exclusive para-selectivity. The present calculations provide deeper insight into the mechanism and origin of regioselectivity of the title reaction.

Synthesis of 4-Substituted-1,2-Dihydroquinolines by Means of Gold-Catalyzed Intramolecular Hydroarylation Reaction of N-Ethoxycarbonyl-N-Propargylanilines

“…electron-rich tri-isopropylphenyl ring on the ligand and the slightly more stro coordinated NTf2 -jointly lower the electrophilicity of the gold center. On the other h the regiodivergent cyclization to the sterically hindered ortho-position to give regioisomeric 1,2-dihydroquinolines 2′k-n resulted governed by the electron-defi ligand features, according to the literature (Table 3) [29]. Very likely, the control of ortho/para site-selectivity in these substrates is the result of the different coordination modes of the gold catalyst influenced by sterics and electronics of the auxiliary ligand.…”

“…The electron-rich tri-isopropylphenyl ring on the ligand and the slightly more strongly coordinated NTf 2 − jointly lower the electrophilicity of the gold center. On the other hand, the regiodivergent cyclization to the sterically hindered ortho -position to give the regioisomeric 1,2-dihydroquinolines 2′k – n resulted governed by the electron-deficient ligand features, according to the literature ( Table 3 ) [ 29 ].…”

Gold(I)‐Catalyzed Intramolecular Hydroarylation of o‐Ethynylarylphosphonium Salt Leading to the Formation of Seven‐ and Six‐membered Phosphacycles

“…Thus, these products should be obtained kinetically and not thermodynamically. We then optimized the transition states of the formation of six‐ or seven‐membered phosphacycles, which should be considered as the rate‐determining step (Scheme S1) [20] . Here, the model ligand with methyl groups were used instead of Dip groups on the NHC to simplify the computation.…”

“…We then optimized the transition states of the formation of six-or seven-membered phosphacycles, which should be considered as the rate-determining step (Scheme S1). [20] Here, the model ligand with methyl groups were used instead of Dip groups on the NHC to simplify the computation. The steric effect of the ligand might be less effective since the substrate locates on the opposite side from the ancillary ligand in gold(I) complexes with a linear coordination.…”

Mechanism and Origin of MAD‐Induced Ni/N‐Heterocyclic Carbene‐Catalyzed Regio‐ and Enantioselective C−H Cyclization of Pyridines with Alkenes

“…DFT calculations were carried out with the Gaussian 09 package for the reaction shown in Scheme using the actual catalyst, substrate, and ligand, and only the bulky tert ‐butyl groups in additive MAD were replaced by methyl groups to keep the computation more efficient. These tert ‐butyl groups are non‐reactive and were indicated in our calculations to be far away from the reaction center, therefore can be reduced safely, as done in previous studies . For easy understanding, the simplified additive is still denoted with MAD.…”