Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies

Abstract

An efficient palladium-catalyzed asymmetric hydrogenation of a variety of unprotected indoles has been developed that gives up to 98% ee using a strong Brønsted acid as the activator. This methodology was applied in the facile synthesis of biologically active products containing a chiral indoline skeleton. The mechanism of Pd-catalyzed asymmetric hydrogenation was investigated as well. Isotope-labeling reactions and ESI-HRMS proved that an iminium salt formed by protonation of the CC bond of indoles was the significant intermediate in this reaction. The important proposed active catalytic Pd−H species was observed with 1 H NMR spectroscopy. It was found that proton exchange between the Pd−H active species and solvent trifluoroethanol (TFE) did not occur, although this proton exchange had been previously observed between metal hydrides and alcoholic solvents. Density functional theory calculations were also carried out to give further insight into the mechanism of Pd-catalyzed asymmetric hydrogenation of indoles. This combination of experimental and theoretical studies suggests that Pd-catalyzed hydrogenation goes through a stepwise outersphere and ionic hydrogenation mechanism. The activation of hydrogen gas is a heterolytic process assisted by trifluoroacetate of Pd complex via a six-membered-ring transition state. The reaction proceeds well in polar solvent TFE owing to its ability to stabilize the ionic intermediates in the Pd−H generation step. The strong Brønsted acid activator can remarkably decrease the energy barrier for both Pd−H generation and hydrogenation. The high enantioselectivity arises from a hydrogen-bonding interaction between N−H of the iminium salt and oxygen of the coordinated trifluoroacetate in the eight-membered-ring transition state for hydride transfer, while the active chiral Pd complex is a typical bifunctional catalyst, effecting both the hydrogenation and hydrogen-bonding interaction between the iminium salt and the coordinated trifluoroacetate of Pd complex. Notably, the Pd-catalyzed asymmetric hydrogenation is relatively tolerant to oxygen, acid, and water.

Shaping the selectivity in heterogeneous hydrogenation by using molecular modification strategies: Experiment and theory

“…Moreover, according to their calculations, an Eley-Rideal type transition state (TS) was identified as a more feasible pathway for the first step hydrogenation, rather than the classical Langmuir-Hinshelwood type. It should be noted that such "non-coordinated" mechanism is very similar to the outer-sphere hydrogenation mechanism in the homogeneous catalysis [43].…”

Regioselective Synthesis of 2‐Arylindoles via Palladium‐Catalyzed Cyclization of Phenylglyoxal and 2‐Anilinoacetophenones with Anilines

“…Then, a second condensation occurs to afford intermediate 1d , which would be in equilibrium with its tautomeric enamine A . This enolic tautomer is activated by the palladium hydride species, forming the intermediate II via an insertion of the double bond into the palladium hydride . Subsequently, the intermediate IV would be formed via Hofmann elimination from III .…”

Chiral Brønsted Acid from Chiral Phosphoric Acid Boron Complex and Water: Asymmetric Reduction of Indoles

“…Notably, a variety of excellent methods for direct asymmetric reduction of N‐unprotected indoles, which is a more step‐economical and powerful strategy to access enantioenriched indolines, has been developed with various catalytic reductive systems (Figure a) . However, all these catalytic systems have similar limitations on the substrates: 1) C2‐aryl‐substituted N‐unprotected indoles failed in these asymmetric reductions;– 2) lack of broad functional‐group compatibility.…”