Copper‐Catalyzed Oxidative C−H Bond Functionalization of N‐Allylbenzamide for Regioselective C−N and C−O Bond Formation

Copper‐catalyzed oxidative couplings of N‐allylbenzamides for C?N and C?O bond formations have been developed through C?H bond functionalization. To demonstrate the utility of this approach, it was applied to the synthesis of β‐aminoimides and imides. To the best of our knowledge, these are the first examples in which different classes of N‐containing compounds have been directly prepared from the readily available N‐allylbenzamides using an inexpensive catalyst/oxidant/base (CuSO₄/TBHP/Cs₂CO₃) system.     

Stereoselective Synthesis of cis‐2,5‐Disubstituted Pyrrolidines via Copper‐Catalyzed Cyclization of Alkenes

An efficient methodology for the stereoselective synthesis of cis‐2,5‐disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis‐2,5‐disubstituted pyrrolidines could be obtained in reasonable yields and with good stereoselectivities in the presence of 4,4′‐di‐tert‐butyl‐2,2′‐bipyridine as ligand and 1‐methyl‐2‐pyrrolidinone as solvent.     

Cascade Mn‐Mediated γ‐Alkylation/oxa‐Michael Addition of Enones with 1,3‐Dicarbonyls

A radical‐based strategy for regioselective γ‐C?C bond formation/oxa‐conjugate addition, forming the tetrahydrobenzofuran core common to many bioactive natural products is described. The technique utilizes readily available enone derivatives and 1,3‐dicarbonyl compounds as coupling partners in an oxidative formal [3+2] cycloaddition mediated by Mn^III. The transformation delivers polycyclic products in good yields and proceeds with complete regiocontrol and excellent stereoselectivity. Sterically encumbered substrates are notably well‐tolerated and bond formation occurs readily to form neopentyl and all‐carbon quaternary centers in good yields. Several stereo‐ and chemoselective transformations of the products are described.     

A General Strategy for the Synthesis of Enantiomerically Pure Azetidines and Aziridines through Nickel‐Catalyzed Cross‐Coupling

In this communication, we report a straightforward synthesis of enantiomerically pure 2‐alkyl azetidines. The protocol is based on a highly regioselective nickel‐catalyzed cross‐coupling of aliphatic organozinc reagents with an aziridine that features a tethered thiophenyl group. Activation by methylation transforms the sulfide into an excellent leaving group and triggers the formation of the 2‐substituted azetidine core structure by cyclization. In addition, we have expanded this concept to the synthesis of enantiomerically pure, terminal alkyl aziridines. Coupling of a TMS‐protected aziridine alcohol, followed by acidic work‐up to remove the silyl group, provides 1,2‐amino alcohol products that are readily cyclized to aziridines. Both of these sequences display excellent functional group tolerance and deliver the desired azetidine and aziridine products in good to excellent yields.     

Highly Enantioselective Copper‐Catalyzed Ring Opening of Oxabicyclic Alkenes with Grignard Reagents

A highly efficient copper‐catalyzed enantioselective ring opening of oxabicylic alkenes with Grignard reagents has been developed by using chiral spiro phosphine ligands. Excellent trans selectivities, good yields, and high enantioselectivities are obtained for a broad range of Grignard reagents under mild reaction conditions. The catalyst system shows an extraordinary activity and the TON of the reaction reaches 9000.     

Asymmetric Synthesis of Spirocyclic β‐Lactams through Copper‐Catalyzed Kinugasa/Michael Domino Reactions

The first copper‐catalyzed highly chemo‐, regio‐, diastereo‐, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne‐tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β‐lactams possessing four contiguous stereocenters, including one quaternary and one tetra‐substituted stereocenter.     

Highly Stereoselective [3+2] Cycloadditions of Chiral Palladium‐Containing N1‐1,3‐Dipoles: A Divergent Approach to Enantioenriched Spirooxindoles

A catalytic asymmetric [3+2] cycloaddition reaction of chiral palladium‐containing N¹‐1,3‐dipoles with methyleneindolinones has been successfully developed. The reaction allows an efficient construction of 3,3′‐pyrrolinyl spirooxindoles with high yields and excellent stereoselectivities (up to 93 % yield, 19:1 d.r. and >99 % ee). A synthetic application of this methodology is demonstrated and a stereocontrol mechanism is proposed.     

Regioselective Ring‐Opening of Amino Acid‐Derived Chiral Aziridines: an Easy Access to cis‐2,5‐Disubstituted Chiral Piperazines

An efficient four‐step synthetic strategy for cis‐2,5‐disubstituted chiral piperazines derived from amino‐acid‐based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF₃ ⋅ OEt₂)‐mediated ring‐opening of less‐reactive N‐Ts chiral aziridines by α‐amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)‐piperazinomycin.     

Enantioselective Copper‐Catalyzed Decarboxylative Propargylic Alkylation of Propargyl β‐Ketoesters with a Chiral Ketimine P,N,N‐Ligand

The first enantioselective copper‐catalyzed decarboxylative propargylic alkylation has been developed. Treatment of propargyl β‐ketoesters with a catalyst, prepared in situ from [Cu(CH₃CN)₄BF₄] and a newly developed chiral tridentate ketimine P,N,N‐ligand under mild reaction conditions, generates β‐ethynyl ketones in good yields and with high enantioselectivities without requiring the pregeneration of ketone enolates. This new process provides facile access to a range of chiral β‐ethynyl ketones in a highly enantioenriched form.     

Efficient Access to Bicyclo[4.3.0]nonanes: Copper‐Catalyzed Asymmetric Silylative Cyclization of Cyclohexadienone‐Tethered Allenes

The creation of three consecutive chiral carbon centers in one step is achieved using Cu‐catalyzed asymmetric silylative cyclization of cyclohexadienone‐tethered allenes. Through regioselective β‐silylation of the allene and subsequent enantioselective 1,4‐addition to cyclohexadienone, this tandem reaction could afford cis‐hydrobenzofuran, cis‐hydroindole, and cis‐hydroindene frameworks with excellent yields (80–98 %) and enantioselectivities (94–98 % ee) bearing vinylsilane and enone substructures. Meanwhile, this mild transformation is generally compatible with a wide range of functional groups, which allows further conversion of the bicyclic products to bridged and tricyclic ring structures.     

An Enantioselective CpxRh(III)‐Catalyzed C−H Functionalization/Ring‐Opening Route to Chiral Cyclopentenylamines

A chiral Cp^xRh^III catalyst system in situ generated from a Cp^xRh^I(cod) precatalyst and bis(o‐toluoyl) peroxide as activating oxidant was developed for a C?H activation/ring‐opening sequence between aryl ketoxime ethers and 2,3‐diazabicyclo[2.2.1]hept‐5‐enes. This transformation provides access to densely functionalized chiral cyclopentenylamines in excellent yields and enantioselectivities of up to 97:3 er. The reported method is also well suitable for asymmetric alkenyl C?H functionalizations of α,β‐unsaturated oxime ethers, furnishing skipped dienes with high levels of enantiocontrol.     

Syntheses and Fully Diastereospecific Photochromic Reactions of Thiophenophan‐1‐enes with Chiral Bridges

Thiophenophan‐1‐enes with chiral polyether bridges were prepared and their diastereospecific photochromic reactions were studied. The coupling reaction of substituted dithienylethenes and various chiral synthons afforded thiophenophan‐1‐enes, namely, bridged dithienylethenes, as single enantiomers without optical resolution, thus indicating that these reactions occurred diastereoselectively. Upon UV irradiation, each optically active thiophenophan‐1‐ene isomerized to the corresponding enantiomer of the closed form and returned to the initial enantiomer of the open form upon visible irradiation. Because thiophenophan‐1‐enes never isomerized to other diastereomers even at a high temperature, they underwent diastereospecific photochromic reactions. Large changes were observed in the measurement of the optical rotations of the solutions of thiophenophan‐1‐enes at 588 nm according to their photochromic reactions. As there was no absorption at this wavelength for both isomers of each thiophenophan‐1‐enes, the nondestructive readout of the photochromic reaction could be carried out by using these chiral thiophenophan‐1‐enes.     

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.     

Enantioselective Synthesis of α‐Aminosilanes by Copper‐Catalyzed Hydroamination of Vinylsilanes

The synthesis of α‐aminosilanes by a highly enantio‐ and regioselective copper‐catalyzed hydroamination of vinylsilanes is reported. The system employs Cu‐DTBM‐SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O‐benzoylhydroxylamines as the electrophilic nitrogen source. This hydroamination reaction is compatible with differentially substituted vinylsilanes, thus providing access to amino acid mimics and other valuable chiral organosilicon compounds.     

Synthesis of Substituted Pyrroles via Copper‐Catalyzed Cyclization of Ethyl Allenoates with Activated Isocyanides

A new method for the synthesis of di‐ and trisubstituted pyrroles via copper‐catalyzed cyclization of ethyl allenoates with activated isocyanides has been developed. In contrast to related annulation reactions previously reported, this new process features a skeletal rearrangement in which the aryl sulfonyl moiety, which functions as the electron‐withdrawing group in the α‐carbon of the isocyanide, was found to migrate to the γ‐carbon of the starting allenoate in the final product for the first time.