Iminyl‐Radicals by Oxidation of α‐Imino‐oxy Acids: Photoredox‐Neutral Alkene Carboimination for the Synthesis of Pyrrolines

The visible‐light‐promoted decarboxylation of α‐imino‐oxy propionic acids for the generation of iminyl radicals has been accomplished through the use of Ir(dFCF₃ppy)₂(dtbbpy)PF₆ as a photoredox catalyst. Different from visible‐light‐promoted homolysis and single‐electron reduction of oxime derivatives, this strategy provides a novel catalytic cycle for alkene carboimination through a sequence comprising N‐radical generation, iminyl radical cyclization, intermolecular conjugate addition to a Michael acceptor, and single‐electron reduction to afford various pyrroline derivatives in an overall redox‐neutral process. The indolizidine alkaloid skeleton could be easily constructed from a pyrroline derivative prepared by this synthetic method.     

Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

The first highly enantioselective phosphine‐catalyzed formal [4+4] annulation has been developed. In the presence of amino‐acid‐derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole‐derived α,β‐unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight‐membered rings by phosphine catalysis.     

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.     

Bifunctional Brønsted Base Catalyst Enables Regio‐, Diastereo‐, and Enantioselective Cα‐Alkylation of β‐Tetralones and Related Aromatic‐Ring‐Fused Cycloalkanones

The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner.     

Catalytic Enantioselective γ‐Selective Additions of 2‐Allylazaarenes to Activated Ketones

Reported herein is the first example of 2‐allylazaarenes in asymmetric catalysis. Highly γ‐selective allylation was demonstrated for activated ketones, including isatins and trifluoromethyl ketones. In the presence of either an amino‐acid‐based tertiary amine or quaternary ammonium salt catalyst, two series of tertiary hydroxy‐containing moieties were installed at the remote δ‐position of azaarenes in good chemical yields, excellent enantioselectivities, and E /Z ratios. The success of current γ‐selective reactions should provide inspiration for expansion to other allylazaarene derivatives and would open up new paradigms for the synthesis of chiral γ‐ and/or δ‐functionalized azaarenes.     

Manipulation of Spiroindolenine Intermediates for Enantioselective Synthesis of 3‐(Indol‐3‐yl)‐Pyrrolidines

By manipulating the reactivity of spiroindolenine species, a sequential Michael/retro‐Mannich/Mannich reaction of ω‐indol‐3‐yl α,β‐unsaturated ketones was developed. In the presence of 10 mol % of a chiral phosphoric acid as the catalyst, a series of 3‐(indol‐3‐yl)‐pyrrolidines were synthesized in high yields (up to 91 %) with excellent stereoselectivities (up to 92 % ee, >19:1 d.r.). The products obtained here undergo diverse functional‐group transformations. The mechanistic proposal of this reaction is supported by DFT calculations.     

Concurrent Asymmetric Reactions Combining Photocatalysis and Enzyme Catalysis: Direct Enantioselective Synthesis of 2,2‐Disubstituted Indol‐3‐ones from 2‐Arylindoles

The combination of photoredox and enzymatic catalysis for the direct asymmetric one‐pot synthesis of 2,2‐disubstituted indol‐3‐ones from 2‐arylindoles through concurrent oxidization and alkylation reactions is described. 2‐Arylindoles can be photocatalytically oxidized to 2‐arylindol‐3‐one with subsequent enantioselective alkylation with ketones catalyzed by wheat germ lipase (WGL). The chiral quaternary carbon center at C2 of the indoles was directly constructed. This mode of concurrent photobiocatalysis provides a mild and powerful strategy for one‐pot enantioselective synthesis of complex compounds. The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way. This reaction is the first example of combining the non‐natural catalytic activity of hydrolases with visible‐light catalysis for enantioselective organic synthesis and it does not require any cofactors.     

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

A new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/Zn^II complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.     

Regioselective Acylation of Cyclic α-Silylallyl Sulphide

Acylation of cyclic α-trimethylsilylallyl sulphide ( 3 ) by reaction with the acid halide catalyzed by aluminum chloride in CH₂Cl₃ at ?78°_C gave compound 4 in good yield with extremely high regio-selectivity.     

Regioselective Functionalization of 7‐Azaindole by Controlled Annular Isomerism: The Directed Metalation‐Group Dance

The regioselective functionalization of 7‐azaindole by controlled annular isomerism employing a directed metalation‐group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6‐substituted derivatives which, in the presence of a catalytic amount of ClCONR₂ promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6‐substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late‐stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.