Wei Hao

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.

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.

Despite significant advancements in ester hydrogenation using homogeneous metal catalysts over the past two decades, the catalytic hydrogenation of sterically hindered α-trisubstituted carboxylic esters remains a formidable challenge. Herein, we present a class of imidazole-based NNP-pincer manganese (Mn) catalysts capable of efficiently hydrogenating α-trisubstituted carboxylic esters to their corresponding β-trisubstituted primary alcohols, which are widely applied in the pharmaceutical and fine-chemical industry. Under catalytic conditions, the imidazole moiety is deprotonated by ^tBuOK to generate a highly reactive anionic Mn-H species with a potassium countercation. Mechanistic studies reveal that the potassium cation in this anionic Mn-H intermediate interacts synergistically with the substrate's carbonyl group and the alkoxide group during hydrogen activation. This cation effect significantly lowers the energy barriers for both hydride transfer and heterolytic H₂ cleavage, thereby enhancing catalytic activity. Leveraging this potent anionic Mn-H catalyst, we achieved the hydrogenation of a diverse array of α-trisubstituted carboxylates (80 examples) under mild conditions.

The asymmetric trans-selective hydrogenation of arenes has long been a significant challenge. In this work, we were able to control the trans/cis selectivity in ruthenium-catalyzed asymmetric hydrogenation of 2,3-disubstituted quinoxalines by varying the catalyst counteranion. Using density functional theory calculations, we investigated the weak interactions─such as CH/π and hydrogen bonding─among the counteranion, the catalyst framework, and the substrate, elucidating the fundamental influence of counteranions on trans/cis selectivity in the asymmetric hydrogenation of quinoxalines.

Due to their strong aromaticity and difficulties in chemo-, regio-, and enantioselectivity control, asymmetric hydrogenation of naphthol derivatives to 1,2,3,4-tetrahydronaphthols has remained a long-standing challenge. Herein, we report the first example of homogeneous asymmetric hydrogenation of naphthol derivatives catalyzed by tethered rhodium-diamine catalysts, affording a wide array of optically pure 1,2,3,4-tetrahydronaphthols in high yields with excellent regio-, chemo-, and enantioselectivities (up to 98% yield and >99% ee). Mechanistic studies with experimental and computational approaches reveal that fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) plays vital roles in the control of reactivity and selectivity, and 1-naphthol is reduced via a cascade reaction pathway, including dearomative tautomerization, 1,4-hydride addition, and 1,2-hydride addition in sequence. A novel synergistic activation mode was proposed in which HFIP assists a synergistic activation of both the hydrogen molecule and naphthol in the presence of a base, and the in situ-generated fleeting keto tautomer is immediately trapped and reduced by the Rh(III)-H species before it escapes from the solvent cage. This protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs. Particularly, optically pure Nadolol, a drug for the treatment of hypertension, angina pectoris, congestive heart failure, and certain arrhythmias, is enantioselectively synthesized for the first time.

Chiral 1,2-bis(2,5-diphenylphospholano)ethane (Ph-BPE) is a class of optimal organic bisphosphine ligands with C₂-symmetry. Ph-BPE with its excellent catalytic performance in asymmetric synthesis has attracted much attention of chemists with increasing popularity and is growing into one of the most commonly used organophosphorus ligands, especially in asymmetric catalysis. Over two hundred examples have been reported since 2012. This review presents how Ph-BPE is utilized in asymmetric synthesis and how powerful it is as a chiral ligand or even a catalyst in a wide range of reactions including applications in the total synthesis of bioactive molecules.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s¹, for energy storage, through the reduction of protons to generate hydrogen^2,3, and for organic synthesis, for the functionalization of unsaturated C–C, C–O and C–N bonds^4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s⁶ but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)⁷. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co–H generation that takes place through a low-valent intermediate.