Monofluoroalkenylation of Dimethylamino Compounds through Radical–Radical Cross‐Coupling

An unprecedented and challenging radical–radical cross‐coupling of α‐aminoalkyl radicals with monofluoroalkenyl radicals derived from gem‐difluoroalkenes was achieved. This first example of tandem C(sp³)?H and C(sp²)?F bond functionalization through visible‐light photoredox catalysis offers a facile and flexible access to privileged tetrasubstituted monofluoroalkenes under very mild reaction conditions. The striking features of this redox‐neutral method in terms of scope, functional‐group tolerance, and regioselectivity are illustrated by the late‐stage fluoroalkenylation of complex molecular architectures such as bioactive (+)‐diltiazem, rosiglitazone, dihydroartemisinin, oleanic acid, and androsterone derivatives, which represent important new α‐amino C?H monofluoroalkenylations.     

Palladium‐Catalyzed Defluorinative Coupling of 1‐Aryl‐2,2‐Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes

The palladium‐catalyzed defluorinative coupling of 1‐aryl‐2,2‐difluoroalkenes with boronic acids is described. Broad functional‐group tolerance arises from a redox‐neutral process by a palladium(II) active species which is proposed to undergo a β‐fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional‐group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Nickel‐Catalyzed Umpolung Arylation of Ambiphilic α‐Bromoalkyl Boronic Esters

A nickel‐catalyzed reductive arylation of ambiphilic α‐bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross‐coupling strategy that complements existing methods for the preparation of densely functionalized alkyl‐substituted organometallic reagents from simple and readily accessible precursors.     

Selective 1,2‐Aryl‐Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis

A highly chemo‐ and regioselective intermolecular 1,2‐aryl‐aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three‐component conjunctive cross‐coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α‐silyl amines could be transferred to α‐amino radicals by photo‐induced single electron transfer step. The radical addition/cross‐coupling cascade reaction proceeds under mild, base‐free and redox‐neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α‐aryl substituted γ‐amino acid derivatives motifs.     

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

A general and practical Pd^II‐catalyzed intermolecular silylation of primary and secondary C?H bonds of α‐amino acids and simple aliphatic acids is reported. This method provides divergent and stereoselective access to a variety of optical pure β‐silyl‐α‐amino acids, which are useful for genetic technologies and proteomics. It can also be readily performed on a gram scale and the auxiliary can be easily removed with retention of configuration. The synthetic importance of this method is further demonstrated by the late‐stage functionalization of biological small molecules, such as (?)‐santonin and β‐cholic acid. Moreover, several key palladacycles were successfully isolated and characterized to elucidate the mechanism of this β?C(sp³)‐H silylation process.     

Ligand‐Enabled Enantioselective C –H Activation of Tetrahydroquinolines and Saturated Aza‐Heterocycles by RhI

The first rhodium(I)‐catalyzed enantioselective intermolecular C –H activation of various saturated aza‐heterocycles including tetrahydroquinolines, piperidines, piperazines, azetidines, pyrrolidines, and azepanes is presented. The combination of a rhodium(I) precatalyst and a chiral monodentate phosphonite ligand is shown to be a powerful catalytic system to access a variety of important enantio‐enriched heterocycles from simple starting materials. Notably, the C –H activation of tetrahydroquinolines is especially challenging due to the adjacent C −H bond. This redox‐neutral methodology provides a new synthetic route to α‐N‐arylated heterocycles with high chemoselectivity and enantioselectivity up to 97 % ee.     

Transition‐Metal‐Mediated and ‐Catalyzed C−F Bond Activation by Fluorine Elimination

The activation of carbon–fluorine (C?F) bonds is an important topic in synthetic organic chemistry. Metal‐mediated and ‐catalyzed elimination of β‐ or α‐fluorine proceeds under milder conditions than oxidative addition to C?F bonds. The β‐ or α‐fluorine elimination is initiated from organometallic intermediates having fluorine substituents on carbon atoms β or α to metal centers, respectively. Transformations through these elimination processes (C?F bond cleavage), which are typically preceded by carbon–carbon (or carbon–heteroatom) bond formation, have been increasingly developed in the past five years as C?F bond activation methods. In this Minireview, we summarize the applications of transition‐metal‐mediated and ‐catalyzed fluorine elimination to synthetic organic chemistry from a historical perspective with early studies and from a systematic perspective with recent studies.     

Nickel‐Catalyzed Chemo‐ and Enantioselective Coupling between Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bicycles

Herein an intramolecular nickel‐catalyzed (4+2) coupling between cyclobutanones and allenes, by C?C cleavage, is reported. The reaction provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches. The reaction is efficient, chemoselective, and pH/redox neutral. Room temperature conditions and low catalyst loadings can be adopted. Excellent enantioselectivity is also achieved.     

Redox‐Neutral Manganese(I)‐Catalyzed C−H Activation: Traceless Directing Group Enabled Regioselective Annulation

A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox‐neutral Mn^I‐catalyzed regioselective synthesis of N‐heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described.     

Ruthenium(II)‐Catalyzed C−H Activation of Imidamides and Divergent Couplings with Diazo Compounds: Substrate‐Controlled Synthesis of Indoles and 3H‐Indoles

Indoles are an important structural motif that is commonly found in biologically active molecules. In this work, conditions for divergent couplings between imidamides and acceptor–acceptor diazo compounds were developed that afforded NH indoles and 3H‐indoles under ruthenium catalysis. The coupling of α‐diazoketoesters afforded NH indoles by cleavage of the C(N₂)?C(acyl) bond whereas α‐diazomalonates gave 3H‐indoles by C?N bond cleavage. This reaction constitutes the first intermolecular coupling of diazo substrates with arenes by ruthenium‐catalyzed C?H activation.     

Synthesis of 2‐Indolyltetrahydroquinolines by Zinc(II)‐Catalyzed Intramolecular Hydroarylation‐Redox Cross‐Dehydrogenative Coupling of N‐Propargylanilines with Indoles

An intramolecular hydroarylation‐redox cross‐dehydrogenative coupling (CDC) of propargylic anilines with indoles proceeded in the presence of zinc(II) catalysts to give 2‐indolyltetrahydroquinolines in good to high yields. Three C?H bonds (two sp² and one sp³) are activated in one shot and these hydrogen atoms are trapped by a propargylic triple bond in the molecule.     

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

An efficient Cp*Co^III‐catalyzed C8‐dienylation of quinoline‐N‐oxides was achieved by employing allenes bearing leaving groups at the α‐position as the dienylating agents. The reaction proceeds by Co^III‐catalyzed C?H activation of quinoline‐N‐oxides and regioselective migratory insertion of the allene followed by a β‐oxy elimination, leading to overall dienylation. Site‐selective C?H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional‐group tolerance. C8‐alkenylation of quinoline‐N‐oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram‐scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.     

(C6F5)3B Catalyzed Chemoselective and ortho‐Selective Substitution of Phenols with α‐Aryl α‐Diazoesters

The development of an efficient method for the site‐selective substitution of unprotected phenols has long been considered as an attractive but challenging task. Herein, we describe a highly chemo‐ and ortho‐selective substitution reaction of phenols with α‐aryl α‐diazoacetates with commercially available (C₆F₅)₃B as the catalyst. This reaction proceeds under simple and mild conditions with high efficiency, it features a wide substrate scope and can be easily scaled up.     

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio‐ and diastereoselective construction of cyclopropanes through C?H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing‐group‐assisted C?H activation strategy was used to realize mild and redox‐neutral Rh^III‐catalyzed C?H activation and cyclopropylation of N‐phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a Rh^V nitrenoid intermediate, and Noyori‐type outer sphere concerted proton‐hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.     

Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Alkenylation and Application to Alkaloid Synthesis

A variety of strained α‐alkylidene‐γ‐lactams were synthesized by palladium(0)‐catalyzed intramolecular C(sp³)?H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for accessing various classes of mono‐ and bicylic alkaloids containing a pyrrolidine ring, as illustrated with the synthesis of an advanced model of the marine natural product plakoridine A and of the indolizidine alkaloid δ‐coniceine.     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.     

Redox‐Neutral α,β‐Difunctionalization of Cyclic Amines

In contrast to the continuously growing number of methods that allow for the efficient α‐functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β‐position. A general redox‐neutral strategy is outlined for amine β‐functionalization and α,β‐difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O‐acetals from simple 1‐(aminomethyl)‐β‐naphthols and 2‐(aminomethyl)‐phenols.     

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by Rh^III‐catalyzed C?H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.     

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

The palladium‐catalyzed asymmetric side‐chain C(α)‐allylation of 2‐alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. Given that the reaction conditions do not require an external base, this catalyst system enabled chemoselective C(α)‐allylation of 2‐alkylpyridines containing α‐carbonyl C?H bonds, which are more acidic than α‐pyridyl C?H bonds.