Chemoselective Amination of Propargylic C(sp3)?H Bonds by Cobalt(II)‐Based Metalloradical Catalysis

Highly chemoselective intramolecular amination of propargylic C(sp³) H bonds has been demonstrated for N‐bishomopropargylic sulfamoyl azides through cobalt(II)‐based metalloradical catalysis. Supported by D_2h‐symmetric amidoporphyrin ligand 3,5‐Di^tBu‐IbuPhyrin, the cobalt(II)‐catalyzed C H amination proceeds effectively under neutral and nonoxidative conditions without the need of any additives, and generates N₂ as the only byproduct. The metalloradical amination is suitable for both secondary and tertiary propargylic C H substrates with an unusually high degree of functional‐group tolerance, thus providing a direct method for high‐yielding synthesis of functionalized propargylamine derivatives.     

C−H Bond Activation by an Imido Cobalt(III) and the Resulting Amido Cobalt(II) Complex

The 3d‐metal mediated nitrene transfer is under intense scrutiny due to its potential as an atom economic and ecologically benign way for the directed amination of (un)functionalised C?H bonds. Here we present the isolation and characterisation of a rare, trigonal imido cobalt(III) complex, which bears a rather long cobalt–imido bond. It can cleanly cleave strong C?H bonds with a bond dissociation energy of up to 92 kcal mol^?1 in an intermolecular fashion, unprecedented for imido cobalt complexes. This resulted in the amido cobalt(II) complex [Co(hmds)₂(NH^tBu)]^?. Kinetic studies on this reaction revealed an H atom transfer mechanism. Remarkably, the cobalt(II) amide itself is capable of mediating H atom abstraction or stepwise proton/electron transfer depending on the substrate. A cobalt‐mediated catalytic application for substrate dehydrogenation using an organo azide is presented.     

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.     

An iron(ii)-based metalloradical system for intramolecular amination of C(sp2)–H and C(sp3)–H bonds: synthetic applications and mechanistic studies

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp²)–H and C(sp³)–H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C–H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp²)–H and C(sp³)–H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications.

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed.     

Palladium(0)/PAr3‐Catalyzed Intermolecular Amination of C(sp3)H Bonds: Synthesis of β‐Amino Acids

An intermolecular C(sp³)? H amination using a Pd⁰/PAr₃ catalyst was developed. The reaction begins with oxidative addition of R₂N? OBz to a Pd⁰/PAr₃ catalyst and subsequent cleavage of a C(sp³)? H bond by the generated Pd? NR₂ intermediate. The catalytic cycle proceeds without the need for external oxidants in a similar manner to the extensively studied palladium(0)‐catalyzed C? H arylation reactions. The electron‐deficient triarylphosphine ligand is crucial for this C(sp³)? H amination reaction to occur.     

A Two‐Coordinate Cobalt(II) Imido Complex with NHC Ligation: Synthesis,Structure, and Reactivity

The synthesis, structural characterization, and reactivity of the first two‐coordinate cobalt complex featuring a metal–element multiple bond [(IPr)Co(NDmp)] ( 4 ; IPr=1,3‐bis(2′,6′‐diisopropylphenyl)imidazole‐2‐ylidene; Dmp=2,6‐dimesitylphenyl) is reported. Complex 4 was prepared from the reaction of [(IPr)Co(η²‐vtms)₂] (vtms=vinyltrimethylsilane) with DmpN₃. An X‐ray diffraction study revealed its linear C? Co? N core and a short Co? N distance (1.691(6) Å). Spectroscopic characterization and calculation studies indicated the high‐spin nature of 4 and the multiple‐bond character of the Co? N bond. Complex 4 effected group‐transfer reactions to CO and ethylene to form isocyanide and imine, respectively. It also facilitated E? H (E=C, Si) σ‐bond activation of terminal alkyne and hydrosilanes to produce the corresponding cobalt(II) alkynyl and cobalt(II) hydride complexes as 1,2‐addition products.     

Catalytic Synthesis of 8‐Membered Ring Compounds via Cobalt(III)‐Carbene Radicals

The metalloradical activation of o‐aryl aldehydes with tosylhydrazide and a cobalt(II) porphyrin catalyst produces cobalt(III)‐carbene radical intermediates, providing a new and powerful strategy for the synthesis of medium‐sized ring structures. Herein we make use of the intrinsic radical‐type reactivity of cobalt(III)‐carbene radical intermediates in the [Co^II(TPP)]‐catalyzed (TPP=tetraphenylporphyrin) synthesis of two types of 8‐membered ring compounds; novel dibenzocyclooctenes and unprecedented monobenzocyclooctadienes. The method was successfully applied to afford a variety of 8‐membered ring compounds in good yields and with excellent substituent tolerance. Density functional theory (DFT) calculations and experimental results suggest that the reactions proceed via hydrogen atom transfer from the bis‐allylic/benzallylic C?H bond to the carbene radical, followed by two divergent processes for ring‐closure to the two different types of 8‐membered ring products. While the dibenzocyclooctenes are most likely formed by dissociation of o‐quinodimethanes (o‐QDMs) which undergo a non‐catalyzed 8π‐cyclization, DFT calculations suggest that ring‐closure to the monobenzocyclooctadienes involves a radical‐rebound step in the coordination sphere of cobalt. The latter mechanism implies that unprecedented enantioselective ring‐closure reactions to chiral monobenzocyclooctadienes should be possible, as was confirmed for reactions mediated by a chiral cobalt‐porphyrin catalyst.     

The mononuclear cobalt(II) complex CoII(DMBDIZ)2(NCS)2, where DMBDIZ is 2,6‐di­methyl­benzo[1,2‐d:4,5‐d′]­di­imidazole

In the title mononuclear cobalt complex, bis(2,6‐di­methyl‐1H,7H‐benzo­[1,2‐d:4,5‐d′]­di­imidazole‐κN³)­bis­(thio­cyanato‐κN)cobalt(II), [Co^II(NCS)₂(DMBDIZ)₂] or [Co(NCS)₂(C₁₀H₁₀N₄)₂], the cobalt(II) ion is coordinated to four N atoms, from two thio­cyanate anions and two DMBDIZ ligands, in a distorted tetrahedral geometry. In the DMBDIZ ligand, the two imine N atoms are positioned cis with respect to one another. The crystal packing of the complex is dominated by both hydrogen bonding, involving two N—H?N and two N—H?S interactions, and aromatic π–π stacking.     

Merging Photochemistry with Electrochemistry: Functional‐Group Tolerant Electrochemical Amination of C(sp3)−H Bonds

Direct amination of C(sp³)?H bonds is of broad interest in the realm of C?H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp³)?H/N?H coupling that exhibits good reactivity with both sp² and sp³ N?H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N?I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C?H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.     

DFT Rationalization of the Diverse Outcomes of the Iodine(III)‐Mediated Oxidative Amination of Alkenes

A computational study of the mechanism for the iodine(III)‐mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO₂Me)₂)₂ and three different representative substrates: styrene, α‐methylstyrene, and (E)‐methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO₂Me)₂)⁺ unit on the double bond, and formation of an intermediate with a single C?I bond and a planar sp² carbocationic center. The major path, leading to 1,2‐diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behavior is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C?H position in the common intermediate. The regioselectivity of this amination depends on the availability of the resonant structures of an alternate carbocationic intermediate. Only in cases where a high electronic delocalization is possible, as in (E)‐methylstilbene, does the allylic amination occur without migration of the double bond.     

A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

Catalytic Enantioselective Intermolecular Benzylic C(sp3)−H Amination

A practical general method for asymmetric intermolecular benzylic C(sp³)?H amination has been developed by combining the pentafluorobenzyl sulfamate PfbsNH₂ with the chiral rhodium(II) catalyst Rh₂(S‐tfptad)₄. Various substrates can be used as limiting components and converted to benzylic amines with excellent yields and high levels of enantioselectivity. Additional key features for the reaction are the low catalyst loading and the ability to remove the Pfbs group under mild conditions to give NH‐free benzylic amines.     

Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂ is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}‐amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.     

Synthesis,crystal structure and infrared spectra of Cu(II) and Co(II) complexes with 4,4′‐dichloro‐2,2′‐[ethylene dioxybis(nitrilomethylidyne)]diphenol

Novel 4,4′‐dichloro‐2,2′‐[ethylenedioxybis(nitrilomethylidyne)]diphenol (H₂L) and its complexes [CuL] and {[CoL(THF)]₂(OAc)₂Co} have been synthesized and characterized by elemental analyses, IR, ¹H‐NMR and X‐ray crystallography. [CuL] forms a mononuclear structure which may be stabilized by the intermolecular contacts between copper atom (Cu) and oxygen atom (O3) to form a head‐to‐tail dimer. In {[CoL(THF)]₂(OAc)₂Co}, two acetates coordinate to three cobalt ions through Co? O? C? O? Co bridges and four µ‐phenoxo oxygen atoms from two [CoL(THF)] units also coordinate to cobalt ions. Copyright © 2008 John Wiley & Sons, Ltd.     

[FeIII(F20‐tpp)Cl] Is an Effective Catalyst for Nitrene Transfer Reactions and Amination of Saturated Hydrocarbons with Sulfonyl and Aryl Azides as Nitrogen Source under Thermal and Microwave‐Assisted Conditions

[Fe^III(F₂₀‐tpp)Cl] (F₂₀‐tpp=meso‐tetrakis(pentafluorophenyl)porphyrinato dianion) is an effective catalyst for imido/nitrene insertion reactions using sulfonyl and aryl azides as nitrogen source. Under thermal conditions, aziridination of aryl and alkyl alkenes (16 examples, 60–95 % yields), sulfimidation of sulfides (11 examples, 76–96 % yields), allylic amidation/amination of α‐methylstyrenes (15 examples, 68–83 % yields), and amination of saturated C? H bonds including that of cycloalkanes and adamantane (eight examples, 64–80 % yields) can be accomplished by using 2 mol % [Fe^III(F₂₀‐tpp)Cl] as catalyst. Under microwave irradiation conditions, the reaction time of aziridination (four examples), allylic amination (five examples), sulfimidation (two examples), and amination of saturated C? H bonds (three examples) can be reduced by up to 16‐fold (24–48 versus 1.5–6 h) without significantly affecting the product yield and substrate conversion.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

A Two‐Coordinate Cobalt(II) Imido Complex with NHC Ligation: Synthesis,Structure, and Reactivity

The synthesis, structural characterization, and reactivity of the first two‐coordinate cobalt complex featuring a metal–element multiple bond [(IPr)Co(NDmp)] ( 4 ; IPr=1,3‐bis(2′,6′‐diisopropylphenyl)imidazole‐2‐ylidene; Dmp=2,6‐dimesitylphenyl) is reported. Complex 4 was prepared from the reaction of [(IPr)Co(η²‐vtms)₂] (vtms=vinyltrimethylsilane) with DmpN₃. An X‐ray diffraction study revealed its linear C Co N core and a short Co N distance (1.691(6) Å). Spectroscopic characterization and calculation studies indicated the high‐spin nature of 4 and the multiple‐bond character of the Co N bond. Complex 4 effected group‐transfer reactions to CO and ethylene to form isocyanide and imine, respectively. It also facilitated E H (E=C, Si) σ‐bond activation of terminal alkyne and hydrosilanes to produce the corresponding cobalt(II) alkynyl and cobalt(II) hydride complexes as 1,2‐addition products.     

Easily Accessible Auxiliary for Palladium‐Catalyzed Intramolecular Amination of C(sp2)H and C(sp3)H Bonds at δ‐ and ε‐Positions

An easily synthesized and accessible N,O‐bidentate auxiliary has been developed for selective C? H activation under palladium catalysis. The novel auxiliary showed its first powerful application in C? H functionalization of remote positions. Both C(sp²)? H and C(sp³)? H bonds at δ‐ and ε‐positions were effectively activated, thus giving tetrahydroquinolines, benzomorpholines, pyrrolidines, and indolines in moderate to excellent yields by palladium‐catalyzed intramolecular C? H amination.     

Bis(sulfonylimide)ruthenium(VI) Porphyrins: X‐ray Crystal Structure and Mechanism of C?H Bond Amination by Density Functional Theory Calculations

The X‐ray crystal structure of [Ru^VI(NMs)₂(tmp)] (Ms=SO₂‐ p‐MeOC₆H₄; tmp=5,10,15,20‐tetramesitylporphyrinato(2?)), a metal sulfonylimide complex that can undergo alkene aziridination and C? H bond amination reactions, shows a Ru?N distance of 1.79(3) Å and Ru‐N‐S angle of 162.5(3)°. Density functional theory (DFT) calculations on the electronic structures of [Ru^VI(NMs)₂(tmp)] and model complex [Ru^VI(NMs)₂(por⁰)] (por⁰=unsubstituted porphyrinato(2?)) using the M06L functional gave results in agreement with experimental observations. For the amination of ethylbenzene by the singlet ground state of [Ru^VI(NMs)₂(por⁰)], DFT calculations using the M06L functional revealed an effectively concerted pathway involving rate‐limiting hydrogen atom abstraction without a distinct radical rebound step. The substituent effect on the amination reactivity of ethylbenzene by [Ru^VI(NX)₂(por⁰)] (X=SO₂‐p‐YC₆H₄ with Y=MeO, Me, H, Cl, NO₂) was examined. Electron‐withdrawing Y groups lower the energy of the LUMOs of [Ru^VI(NX)₂(por⁰)], thus facilitating their interaction with the low‐lying HOMO of the ethylbenzene C? H bond and hence increasing the reactivity of [Ru^VI(NX)₂(por⁰)]. DFT calculations on the amination/aziridination reactions of [Ru^VI(NSO₂C₆H₅)₂(por⁰)] with pent‐4‐enal, an aldehyde substrate bearing acyl, homoallylic, and allylic C? H bonds and a C?C bond, revealed a lower reaction barrier for the amination of the acyl C? H bond than for both the amination of the other C? H bonds and aziridination of the C?C bond in this substrate.     

Copper‐Catalyzed C(sp3)−H Amidation: Sterically Driven Primary and Secondary C−H Site‐Selectivity

Undirected C(sp³)?H functionalization reactions often follow site‐selectivity patterns that mirror the corresponding C?H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C?H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C?H bonds over tertiary and benzylic C?H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C?H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N₃. Mechanistic and DFT studies indicate that C?H amidation involves H‐atom abstraction from R‐H substrates by nitrene intermediates [Cu](κ²‐N,O‐NC(O)Ar) to provide carbon‐based radicals R^. and copper(II)amide intermediates [Cu^II]‐NHC(O)Ar that subsequently capture radicals R^. to form products R‐NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C?H amidation selectivity in the absence of directing groups.