Asymmetric reductive amination (ARA) of a prochiral carbonyl compound with an amine using a H2/hydrogen surrogate is a concise and operationally simple method for the synthesis of chiral amines. ARA proceeds via condensation of a carbonyl group with an amine/ammonia followed by the enantioselective reduction of the generated intermediate. The activation of reductant and stereoselective transfer of hydrogen to intermediate imine/enamine is often mediated by a chiral transition metal catalyst. Considering the wide applications of enantiopure amines in pharmaceuticals, agrochemicals, and materials, the development of effective catalysts for ARA has been intensively pursued in the last two decades. Since the first report by Blaser in 1999, this key research area has grown significantly in recent years, as reflected by the advances in catalyst design, diversifying substrate scope and better mechanistic understanding. Several highly efficient and general ARA methodologies applicable to challenging carbonyl and amine partners have been demonstrated, providing ready access to a variety of enantiopure amines. In this Review, we present the recent progress in ARA featuring diverse carbonyl and amine partners employing transition metal-catalysts. This Review provides an organized and critical discussion on catalyst engineering and evolution, expanding susbstrate scope and mechanistic insights. To conclude, the remaining challenges and opportunities in ARA are also highlighted.

A Cp*Ir(III) complex (1) of a newly designed ligand L 1 featuring a proton-responsive pyridyl(benzamide) appended on N-heterocyclic carbene (NHC) has been synthesized. The molecular structure of 1 reveals a dearomatized form of the ligand. The protonation of 1 with HBF 4 in tetrahydrofuran gives the corresponding aromatized complex [Cp*Ir(L 1 H)Cl]BF 4 (2). Both compounds are characterized spectroscopically and by X-ray crystallography. The protonation of 1 with acid is examined by 1 H NMR and UV-vis spectra. The proton-responsive character of 1 is exploited for catalyzing α-alkylation of ketones and β-alkylation of secondary alcohols using primary alcohols as alkylating agents through hydrogen-borrowing methodology. Compound 1 is an effec-tive catalyst for these reactions and exhibits a superior activity in comparison to a structurally similar iridium complex [Cp*Ir(L 2 )Cl]PF 6 (3) lacking a proton-responsive pendant amide moiety. The catalytic alkylation is characterized by a wide substrate scope, low catalyst and base loadings, and a short reaction time. The catalytic efficacy of 1 is also demonstrated for the syntheses of quinoline and lactone derivatives via acceptorless dehydrogenation, and selective alkylation of two steroids, pregnenolone and testosterone. Detailed mechanistic investigations and DFT calculations substantiate the role of the proton-responsive ligand in the hydrogen-borrowing process.À OH/=O, À CH 2 /=CH and À NH/ = N motifs on pyridine, [25][26][27] bipyridine, [28][29][30][31][32] bipyrimidine [33] and azole-pyridine/ pyrimidine [34][35][36][37] are particularly effective. Some of the representative examples that have been employed for catalyzing (de) hydrogenation and alkylation reactions are given in Scheme 1. Yamaguchi and co-workers reported a Cp*Ir(III) compound with

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The two donor modules of an annelated pyridyl–mesoionic carbene ligand (aPmic) have different σ- and π-bonding characteristics leading to its electronic asymmetry. A Pd­(II) complex 1 featuring aPmic catalyzes the oxidation of a wide range of terminal olefins to the corresponding methyl ketones in good to excellent yields in acetonitrile. The catalytic reaction is proposed to proceed via syn-peroxypalladation and a subsequent rate-limiting 1,2-hydride shift, which is supported by kinetic studies. The electronic asymmetry of aPmic renders a well-defined coordination sphere at Pd. The favored arrangement of reactants on the metal center features an olefin trans to the pyridyl module and a t butylperoxide trans to the carbene. This arrangement gains added stability by the π-delocalization paved by the compatible orbitals on Pd, the pyridyl module, and the olefin that is perpendicular to the Pd­(aPmic) plane. The π-interactions are absent in an alternate arrangement wherein the olefin is trans to the carbene. Density functional theory studies reveal the matching orbital overlaps responsible for the preferred arrangement over the other. This work provides an orbital description for the electronic asymmetry of aPmic.

A Cp*Ir­(III) complex (1) bearing a proton-responsive hydroxy unit on an annulated imidazo­[1,2-a]­[1,8]­naphthyridine based mesoionic carbene scaffold was synthesized by two different synthetic routes. The molecular structure of 1 revealed an anionic lactam form of the ligand. The acid–base equilibrium between the lactam-lactim tautomers on the ligand scaffold was examined by 1H NMR and UV–vis spectra. The pK a of the appendage −OH group in the lactim form of 1 was estimated to assess the proton transfer property of the catalyst. The catalytic efficacy of 1 for reductive amination of aldehyde was evaluated by utilizing three different hydrogen sources: molecular H2, i PrOH/KO t Bu combination, and HCOOH/Et3N (5:2) azeotropic mixture. The HCOOH/Et3N (5:2) azeotropic mixture protocol was found to be the best among the three different hydrogenation methods. Catalyst 1 hydrogenates imines chemoselectively over carbonyls under the reaction conditions. A range of aldehydes was reductively aminated to the corresponding secondary amines using the HCOOH/Et3N (5:2) azeotropic mixture. Further, catalyst 1 showed high efficiency for the reduction of a wide variety of N-heterocyclic imine derivatives. The lactam-lactim tautomerization of the ligand system is proposed for direct hydrogenation, whereas only the lactam form operates in the strongly basic medium ( i PrOH/KO t Bu). Under HCOOH/Et3N (5:2) conditions, the lactam scaffold is not protonated; rather, an outer-sphere hydride transfer from formate to the Ir is proposed, which is supported by 1H NMR and DFT calculations. Finally, ligand-promoted hydride transfer from metal-hydride to the protonated imine affords the corresponding amine. A close agreement between the experimentally estimated and computed thermodynamic/kinetic parameters gives credence to the metal-ligand cooperative mechanism for the imine hydrogenation reaction using the HCOOH/Et3N (5:2) azeotropic mixture.