Qing‐Hua Fan

Homogeneous and heterogeneous catalysis represent two frontiers and core areas of research in organic synthesis. Historically, these two catalytic regimes have developed along parallel, largely independent trajectories. Recognizing their inherent complementarity, particularly in terms of activity, selectivity, and recoverability, breaking down the barriers between homogeneous and heterogeneous catalysis to construct novel catalytic systems that integrate high activity, excellent selectivity, robust stability, and ease of recovery has long been a pursued goal in catalysis science. As an emerging strategy, homogeneous–heterogeneous integrated catalysis has opened new avenues for addressing this challenge. This review systematically summarizes cutting‐edge advances in this field from four distinct strategic perspectives: (i) Mixed homogeneous–heterogeneous dual catalytic systems; (ii) Heterogeneous catalyst‐promoted homogeneous catalytic systems; (iii) Homogeneous–heterogeneous bifunctional catalytic systems; and (iv) Switchable homogeneous–heterogeneous catalytic systems. By highlighting representative examples and mechanistic insights, this review also aims to provide new insights into the efficient transformation of challenging substrates and the construction of complex, high‐value chiral compounds in organic synthesis.

The manganese‐catalyzed asymmetric transfer hydrogenation of ketones with chiral N ₆ ‐macrocyclic ligands is reported. Employing 2‐propanol as the hydrogen source, a broad range of chiral alcohols were obtained with excellent yields and enantioselectivities (up to 99% yield and 99% ee) under mild conditions with a catalyst loading of 1 mol %. Density functional theory calculations reveal that an isopropanol molecule participates in the transition states, and multiple noncovalent interactions among the macrocyclic ligand, the isopropanol molecule, and the ketone substrate exist, accounting for the unique macrocyclic effect and revealing the origin of product chirality. Moreover, an investigation of iridium‐catalyzed asymmetric transfer hydrogenation using these chiral N ₆ ‐macrocyclic ligands (2 mol %) demonstrates the superior performance of the manganese catalysts in comparison with their iridium counterparts.

We report the first solvent-controlled chemoselective asymmetric hydrogenation of 2,8'-bisquinolines using chiral Ru/N-sulfonylated diamine complexes. By simply switching the solvent from dichloromethane to methanol, either chiral 1',2',3',4'-tetrahydrobisquinolines or 1,1',2,2',3,3',4,4'-octahydrobisquinolines were obtained in high yields with excellent enantioselectivities. The methodology was successfully applied to scale-up syntheses and the preparation of a new C₁-symmetric N-heterocyclic carbene ligand. Preliminary mechanistic study revealed that an intramolecular hydrogen bond in the tetrahydroquinoline intermediate is the key factor governing the chemoselectivity, which can be disrupted in protic solvents.

The enantiodivergent synthesis of R ‐ and S ‐configured tetrahydroquinoxaline derivatives holds significant importance in pharmaceutical and bioorganic chemistry. In this work, we achieved precise control over the R/S selectivity in the ruthenium‐catalyzed asymmetric hydrogenation of 2‐alkyl‐substituted quinoxalines by modulating the catalyst counteranion. Specifically, a chiral diamine–ruthenium complex bearing a BArF counteranion afforded the R ‐configured product. Remarkably, the product chirality was readily inverted by switching to racemic phosphate counteranion. Density functional theory (DFT) calculations identified various weak non‐covalent interactions (such as CH/π and hydrogen bonding) between the counteranion, catalyst, and substrate, revealing the fundamental mechanism of enantioselectivity inversion.

Regioselective hydrogenation of a single aromatic ring in naphthalene derivatives represents a persistent challenge in synthetic chemistry, particularly when aiming for selective reduction of the functionalized ring. Herein, we report the first heterogeneous Pd-catalyzed hydrogenation of P^V-substituted naphthalene derivatives using a commercially available and recyclable Pd/Al₂O₃ catalyst. Unusual regioselectivity was observed during the hydrogenation of naphthalen-1-yl phosphine oxides, leading to 1,2,3,4-tetrahydronaphthalen-1-yl phosphine oxides with high regioselectivity (up to >95:5 rr) and yield (up to 99%). In contrast, shifting the P^V-group to the C2-position resulted in a reversal of regioselectivity, affording 5,6,7,8-tetrahydronaphthalen-2-yl phosphine oxides with similarly high selectivity and efficiency. This practical method was successfully applied to the synthesis of a novel chiral P,N-ligand and an H₈-Cy-BINAP-type phosphine ligand, underscoring its significant synthetic utility. Mechanistic investigations suggest that the reaction proceeds via a tandem process including 3,4-hydride and subsequent 1,2-hydride additions, with unusual regioselectivity likely arising from a combination of electronic and steric effects. This strategy is anticipated to provide a general approach for the regioselective hydrogenation of functionalized naphthalene derivatives.

The precise control of chemo-, regio- and enantioselectivity in the transition-metal-catalyzed hydrogenation of naphthylamine derivatives has remained a long-standing challenge, stemming from their inherent high aromaticity and the potential for catalyst poisoning by amine groups. Herein, we report the first highly efficient homogeneous hydrogenation of naphthylamine derivatives, enabled by a chiral tethered rhodium-diamine complex. This method provides direct and practical access to a broad range of valuable chiral 1,2,3,4-tetrahydronaphthylamine derivatives from readily available naphthylamine feedstocks. Its extensive synthetic utility is further demonstrated by the concise synthesis of several chiral drugs and bioactive molecules.

A highly efficient asymmetric hydrogenation of tetrahydro‐γ‐carboline derivatives catalyzed by phosphine‐free ruthenium diamine catalysts has been developed, providing the corresponding cis‐hexahydro‐γ‐carbolines with excellent enantioselectivities and diastereoselectivities (up to 99% ee and >20:1 dr). Furthermore, this catalytic protocol is applicable to the gram‐scale synthesis of cardioprotective drug (‐)‐stobadin.

Chiral N,N′-diaryl vicinal diamines have been synthesized enantioselectively via Cp*Rh-catalyzed tandem reductive amination/asymmetric transfer hydrogenation of quinoxaline-2-carbaldehydes with anilines using HCO₂H/NEt₃ (5/2) as the hydrogen source.

In the past several decades, hydrogenation of naphthol derivatives catalyzed by heterogeneous metal catalysts has been widely reported, but precise control of chemo‐, regio‐, and enantioselectivity remains an unresolved challenge. Herein we report the first homogeneous chemo and enantioselective transfer hydrogenation of 1‐naphthol derivatives catalyzed by tethered rhodium‐diamine catalysts with HCOONa reductant affording a broad range of 1‐tetralones and chiral 1,2,3,4‐tetrahydro‐1‐nanphols in high yields with excellent chemo and enantioselectivities, respectively. Preliminary mechanistic study reveals that 1‐naphthol is reduced via a sequential reaction pathway including dearomative tautomerization, 1,4‐hydride addition, and 1,2‐hydride addition in sequence. 1,1,1,3,3,3‐Hexafluoroisopropanol (HFIP) plays vital roles in controlling the reactivity and chemoselectivity of reduction of 1‐naphthols to cyclic ketones. A chemoselectivity switch could be achieved by simply changing the composition of solvent in the second‐step reduction of this one‐pot sequential reaction. This method was applied for the gram‐scale preparation of levobunolol, demonstrating the potential application of this methodology in organic synthesis.