Enantioselective C(sp3)–H Amidation of Thioamides Catalyzed by a CobaltIII/Chiral Carboxylic Acid Hybrid System

Recent advances in Cp^xM^III catalysis (M=Co, Rh, Ir) have enabled a variety of enantioselective C(sp²)?H functionalization reactions, but enantioselective C(sp³)?H functionalization is still largely unexplored. We describe an asymmetric C(sp³)?H amidation of thioamides using an achiral Co^III/chiral carboxylic acid hybrid catalytic system, which provides easy and straightforward access to chiral β‐amino thiocarbonyl and β‐amino carbonyl building blocks with a quaternary carbon stereocenter.     

Rhodium(III)‐Catalyzed Enantiotopic C−H Activation Enables Access to P‐Chiral Cyclic Phosphinamides

Compounds with stereogenic phosphorus atoms are frequently used as ligands for transition‐metal as well as organocatalysts. A direct catalytic enantioselective method for the synthesis of P ‐chiral compounds from easily accessible diaryl phosphinamides is presented. The use of rhodium(III) complexes equipped with a suitable atropochiral cyclopentadienyl ligand is shown to enable an enantiodetermining C−H activation step. Upon trapping with alkynes, a broad variety of cyclic phosphinamides with a stereogenic phosphorus(V) atom are formed in high yields and enantioselectivities. Moreover, these can be reduced enantiospecifically to P ‐chiral phosphorus(III) compounds.     

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.     

Enantioselective Formal C(sp3)−H Bond Activation in the Synthesis of Bioactive Spiropyrazolone Derivatives

Herein, we report the first enantioselective annulation of α‐arylidene pyrazolones through a formal C(sp³)?H activation under mild conditions enabled by highly variable Rh^III‐Cp^x catalysts. The method has a wide substrate scope and proceeds with good to excellent yields and enantioselectivities. Its synthetic utility was demonstrated by the late‐stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Preliminary biological investigations also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.     

Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C−H Amidations of Phosphine Oxides

An enantioselective C−H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert‐leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P‐chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P‐chiral phosphorus(III) compounds.     

Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds

Described here is a direct catalytic asymmetric functionalization of unactivated alkyl indoles using organocatalysis. In the presence of an effective chiral urea catalyst and a phosphoric acid additive, the intermolecular C?C bond formation between alkyl indoles and trifluoropyruvates proceeded with high efficiency and enantiocontrol. Unlike previous asymmetric C(sp³?H) functionalizations of α‐azaarenes, this process does not require the use of either a strong base or an electron‐deficient substrate. The excellent enantiocontrol is particularly noteworthy in view of the severe background reaction as well as the complete inability of other types of catalysts evaluated. Control experiments, kinetic studies, and DFT calculations provided important insights into the mechanism.     

A Bulky Chiral N‐Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C−H Functionalizations of Indoles and Pyrroles

An enantioselective nickel(0)‐catalyzed C?H functionalization of indoles and pyrroles that does not require the typical Lewis basic directing groups is disclosed. The reaction provides access to valuable tetrahydropyridoindoles and tetrahydroindolizines in high yields and enantioselectivity under mild reaction conditions. The process is characterized by a clear endo‐cyclization preference to yield the sought‐after six‐membered‐ring products. Key for the success of the activation and selectivity in the cyclization was the development of a novel chiral SIPr carbene ligand analogue with very bulky flanking groups.     

Catalytic Enantioselective Intramolecular C(sp3)−H Amination of 2‐Azidoacetamides

An enantioselective ring‐closing C(sp³)?H amination of 2‐azidoacetamides is catalyzed by a chiral‐at‐metal ruthenium complex and provides chiral imidazolidin‐4‐ones in 31–95 % yield, with enantioselectivities of up to 95 % ee, and at catalyst loadings down to 0.1 mol % (turnover number (TON)=740). To our knowledge, this is the first example of a highly enantioselective C(sp³)?H amination with aliphatic azides. Mechanistic experiments reveal the importance of the amide group, which presumably enables initial bidentate coordination of the 2‐azidoacetamides to the catalyst. DFT calculations show that the transition state leading to the major enantiomer features a better steric fit and favorable π–π stacking between the substrate and the catalyst framework.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

PdII‐Catalyzed Regio‐ and Enantioselective Oxidative C−H/C−H Cross‐Coupling Reaction between Ferrocenes and Azoles

Asymmetric C?H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C?H/C?H cross‐coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C?H bond cleavage of azoles is likely proceeding through a S_EAr process and may not be a turnover limiting step.