Enantio‐ and Diastereoselective Hydrofluorination of Enals by N‐Heterocyclic Carbene Catalysis

In contrast to well‐established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox‐neutral conditions. Reported here is the highly enantio‐ and diastereoselective hydrofluorination of enals by an asymmetric β‐protonation/α‐fluorination cascade catalyzed by N‐heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.     

N‐Heterocyclic Carbene‐Catalyzed α‐Alkylation of Ketones with Primary Alcohols

Several N‐heterocyclic carbene precursors are synthesized and used in the α‐alkylations of ketones with primary alcohols. With the assistance of a base, these N‐heterocyclic carbenes can catalyze the reaction smoothly to furnish dialkylated ketones in good‐to‐excellent yields.     

Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.     

Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

While the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high‐nucleophilicity N‐heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).     

Photoredox‐Catalyzed Site‐Selective α‐C(sp3)−H Alkylation of Primary Amine Derivatives

The synthetic utility of tertiary amines to oxidatively generate α‐amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site‐selective α‐functionalization of primary amine derivatives through the generation of α‐amino radical intermediates. Employing visible‐light photoredox catalysis, primary sulfonamides are coupled with electron‐deficient alkenes to efficiently and mildly construct C?C bonds. Interestingly, a divergence between intermolecular hydrogen‐atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site‐selectivity.     

N‐Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β‐Unsaturated Amides

Concerted nucleophilic aromatic substitution (CS_NAr) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CS_NAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N‐heterocyclic carbene (NHC)‐catalyzed intramolecular cyclization of acrylamides that contain a 2‐fluorophenyl group on the nitrogen through a CS_NAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin‐2‐one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (C_ipso‐C_β)→ σ*(C_ipso‐F) interaction critically contributes to the stabilization of the transition state for the cyclization.     

N‐Heterocyclic Carbene Catalyzed Synthesis of δ‐Sultones via α,β‐Unsaturated Sulfonyl Azolium Intermediates

A limited array of reactive intermediates have enabled a wealth of discoveries in N‐heterocyclic carbene organocatalysis. In this study, the viability of α,β‐unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3‐dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ‐sultones (18 examples) in good yields (40–88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,β‐unsaturated sulfonyl azolium species.     

N‐Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles

Highly enantioselective [3+3] and [3+4] annulations of isatin‐derived enals with ethynylethylene carbonates and ethynyl benzoxazinanones are enabled by NHC/cooper cooperative catalysis, leading to a big library of spirooxindole derivatives in high structural diversity and enantioselectivity (up to 99 % ee). Both reactions represent a nicely synergistic integration of NHC and copper catalysis, in which both catalysts activate the substrates and the chiral NHC perfectly controls the stereochemistry.     

Cyclic (Aryl)(Amido)Carbenes: NHCs with Triplet‐like Reactivity

The synthesis and study of a library of cyclic (aryl)(amido)carbenes (CArAmCs), which represent a class of electrophilic NHCs that feature low calculated singlet‐triplet gaps (ΔE_ST=19.9 kcal mol^?1; B3LYP/def2‐TZVP) and exhibit reactivity profiles expected from triplet carbenes, are described. The electrophilic properties of the CArAmCs were quantified by analyzing their respective selenium adducts, which exhibited the largest downfield ⁷⁷Se NMR chemical shifts (up to 1645 ppm) measured for any NHC derivative known to date, as well as their Ir carbonyl complexes, from which large Tolman electronic parameter (TEP) values (up to 2064 cm^?1) were ascertained. The CArAmCs were found to engage in reactions that are typically observed with triplet carbenes, including C?H insertions, [2+1] cycloadditions with alkenes as well as alkynes, and spontaneous oxidation upon exposure to oxygen.     

Fusing Dicarbollide Ions with N‐Heterocyclic Carbenes

Discovered by Hawthorne in 1965, dicarbollide ions are an intriguing class of nido ‐carboranes that mimic the behavior of the cyclopentadienyl anion. Herein, we show that it is possible to directly link the dicarbollide ion to an N‐heterocyclic carbene (NHC) to form an isolable N‐dicarbollide‐substituted NHC dianion. This molecule can be accessed by the sequential double deprotonation of a mono‐nido ‐carboranyl imidazolium zwitterion. As revealed by a single‐crystal X‐ray diffraction study, the first deprotonation leads to a monoanionic dicarbollide ion that adopts a bis(dicarbollide) structure in the solid state. Subsequent deprotonation of this monoanion leads to the first N‐dicarbollide NHC, which was fully characterized by multinuclear NMR spectroscopy as well as single‐crystal X‐ray diffraction.     

Transition‐Metal‐Free Hydrogen Autotransfer: Diastereoselective N‐Alkylation of Amines with Racemic Alcohols

A practical method for the synthesis of α‐chiral amines by alkylation of amines with alcohols in the absence of any transition‐metal catalysts has been developed. Under the co‐catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert‐butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium‐labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert‐butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Selective α‐Monomethylation by an Amine‐Borane/N,N‐Dimethylformamide System as the Methyl Source

A new and practical α‐monomethylation strategy using an amine‐borane/N,N‐dimethylformamide (R₃N‐BH₃/DMF) system as the methyl source was developed. This protocol has been found to be effective in the α‐monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R₃N‐BH₃ donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH₂‐, CD₂H‐, and CD₃‐ units using Me₂NH‐BH₃/d₇‐DMF, Me₃N‐BD₃/DMF and Me₃N‐BD₃/d₇‐DMF systems, respectively. Further application of this method to the facile synthesis of anti‐inflammatory flurbiprofen and its varied deuterium‐labeled derivatives was demonstrated.     

N‐Heterocyclic Carbene Catalyzed Enantioselective α‐Fluorination of Aliphatic Aldehydes and α‐Chloro Aldehydes: Synthesis of α‐Fluoro Esters,Amides, and Thioesters

The asymmetric fluorination of azolium enolates that are generated from readily available simple aliphatic aldehydes or α‐chloro aldehydes and N‐heterocyclic carbenes (NHCs) is described. The process significantly expands the synthetic utility of NHC‐catalyzed fluorination and provides facile access to a wide range of α‐fluoro esters, amides, and thioesters with excellent enantioselectivity. Pyrazole was identified as an excellent acyl transfer reagent for catalytic amide formation.     

(NHC)NiH‐Catalyzed Intermolecular Regio‐ and Diastereoselective Cross‐Hydroalkenylation of Endocyclic Dienes with α‐Olefins

Highly selective cross‐hydroalkenylations of endocyclic 1,3‐dienes at the least substituted site with α‐olefins were achieved with a set of neutral (NHC)Ni^IIH(OTf) catalysts and cationic Ni^II catalysts with a novel NHC ligand. Under heteroatom assistance, skipped dienes were obtained in good yields, often from equal amounts of the two substrates and at a catalyst loading of 2–5 mol %. Rare 4,3‐product selectivity (i.e., with the H atom at C4 and the alkenyl group at C3 of the diene) was observed, which is different from the selectivity of known dimerizations of α‐olefins with both acyclic Co and Fe systems. The influence of the various substituents on the NHC, 1,3‐diene, and α‐olefin on the chemo‐, regio‐, and diastereoselectivity was studied. High levels of chirality transfer were observed with chiral cyclohexadiene derivatives.     

N‐Heterocyclic Carbene Stabilized Boryl Radicals

The reaction of the 2‐(trimethylsilyl)imidazolium triflate 9 with diarylboron halides (4‐R‐C₆H₄)₂BX (R=H, X=Br; R=CH₃, X=Cl; R=CF₃, X=Cl) afforded the NHC‐stabilized borenium cations 10 a – c . Cyclic voltammetry revealed a linear correlation between the Hammett parameter σ _p of the para substituent and the half‐wave potential. Chemical reduction with decamethylcobaltocene, [(C₅Me₅)₂Co], furnished the corresponding radicals 11 a – c ; their characterization by EPR spectroscopy confirmed the paramagnetic character of 11 a – c , with large hyperfine coupling constants to the boron isotopes ¹¹B and ¹⁰B, while delocalization of the unpaired electron into the NHC is negligible. DFT calculations of the percentage of spin density distribution between the carbene (NHC) and the boryl fragments (BR₂) revealed for 11 a – c a spin density ratio (BR₂/NHC) of ca. 9:1, which underlines their distinct boryl radical character. The molecular structure of the most stable species 11 c was established by X‐ray diffraction analysis.