Electrostatically tuned phenols: a scalable organocatalyst for transfer hydrogenation and tandem reductive alkylation of N-heteroarenes

Abstract

One of the fundamental aims in catalysis research is to understand what makes a certain scaffold perform better as a catalyst than another. For instance, in nature enzymes act as versatile catalysts, providing a starting point for researchers to understand how to achieve superior performance by positioning the substrate close to the catalyst using non-covalent interactions. However, translating this information to a non-biological catalyst is a challenging task. Here, we report a simple and scalable electrostatically tuned phenol (ETP) as an organocatalyst for transfer hydrogenation of N-arenes using the Hantzsch ester as a hydride source. The biomimetic catalyst (1-5 mol%) displays potential catalytic activity to prepare diverse tetrahydroquinoline derivatives with good to excellent conversion under ambient reaction conditions. Kinetic studies reveal that the ETP is 130-fold faster than the uncharged counterpart, towards completion of the reaction. Control experiments and NMR spectroscopic investigations elucidate the role of the charged environment in the catalytic transformation.

Fig. 1. (A) Different phenol based catalytic system designs; (B) synthesis of electrostatically tuned phenols.

Fig. 2. Evaluation of metal-free catalysts for the transfer hydrogenation of quinoline. ^aUnless otherwise mentioned all the reactions are carried out with catalyst (5 mol%), quinoline (0.5 mmol) with HE (2.5 mol eq.) using dry DCE (1 mL) as the solvent at 60 °C. ^bReaction was carried out at room temperature (28–30 °C).

Fig. 3. Chemoselective transfer hydrogenation of N-arenes using ETP-6 as catalyst. ^aUnless otherwise mentioned all the reactions are carried out with catalyst (5 mol%), substrate (0.5 mmol) with HE (2.5 mol eq.) using solvent (1 mL) at 60 °C for 10 min. The conversions mentioned in the parentheses are the reactions carried out at room temperature (28–30 °C) for 7 h, keeping all the other parameters same. ^bSubstrate: (E)-2-(3,4-dimethoxystyryl) quinoline has an additional olefinic bond and requires HE in 3.5 mol eq. with all other parameters kept the same.

Fig. 4. (A) Proposed mechanism for ETP-6 catalyzed transfer hydrogenation of N-arenes, (B) control experiments for mechanistic investigations, (C) recycling process of the Hantzsch ester, (D and E) ¹H NMR spectra for the interaction study of ETP-6 and quinoline.

Fig. 5. Scaling up, separation and purification process for the transfer hydrogenation of quinoline using ETP-6 as the catalyst in the presence of HE.

Fig. 6. One-pot reductive alkylation of N-arenes using ETP-6 as the catalyst. ^aUnless otherwise mentioned all the reactions are carried out with catalyst (5 mol%), substrate quinoline (0.5 mmol), aldehyde (0.5 mmol) with HE (3.5 mol eq.) using DCE (1 mL) at 60 °C for 1 h.