Bond Halogenation Research Articles

Synthesis and Reactivity of s-Aryltetrazines Palladacycles Toward a Direct o-Aryl C–H Bond Halogenation Achieved by Electrocatalysis

Synthesis and Reactivity of <i>s</i>-Aryltetrazines Palladacycles Toward a Direct <i>o</i>-Aryl C–H Bond Halogenation Achieved by Electrocatalysis

C-H BOND HALOGENATION OF BENZOXAZINONES BY PALLADIUM CATALYSTS

In this research, palladium-catalyzed C-H bond halogenation of benzoxazinone derivatives has been achieved. This approach shows high regioselectivity and wide substrate scope, the products are obtained in moderate to good yields. The plausible mechanism was discussed, the reaction may have gone through a PdII/PdIV/PdII process. This protocol provides a simple and effective synthesis pathway for various halogenated benzoxazinone derivatives.

C-H BOND HALOGENATION OF BENZOXAZINONES BY PALLADIUM CATALYSTS

In this research, palladium-catalyzed C-H bond halogenation of benzoxazinone derivatives has been achieved. This approach shows high regioselectivity and wide substrate scope, the products are obtained in moderate to good yields. The plausible mechanism was discussed, the reaction may have gone through a PdII/PdIV/PdII process. This protocol provides a simple and effective synthesis pathway for various halogenated benzoxazinone derivatives.

Synthesis of Novel Pyrazine-Substituted 1H-Pyrrole-2-carboxamides and Related Tethered Heterocycles

AbstractAs part of a drug discovery program, 4-pyrazin-2-yl-1H-pyrrole-2-carboxamides were accessed along with a number of bicyclic analogues. Routes to these compounds were largely absent from the scientific literature. The synthesis of a 4-(pyrazin-2-yl)-1H-pyrrole-2-carboxamide and several fused bicyclic analogues all using standard procedures (SNAr, borylation, C–C cross couplings, hydrolysis, amide bond formation, cyclisation, halogenation, and alkylation) from readily available starting materials is reported. The synthetic sequences range from 4–12 steps per final compound, with yields of isolated intermediates ranging from 20 to ∼100%.

Recent Update on Transition Metal‐Free C(sp2)−H Bond Halogenation in (Hetero) Arenes

AbstractHalogen incorporated arenes and heteroarenes are often used as useful intermediates as well as target products in organic synthesis. Often, C−H bond halogenation is attempted using transition metals (Pd, Cu, Au, Rh etc.). However, keeping the environmental concerns in mind, transition metal free protocols are more relevant and essential in recent times. In this context, improvised methods are widely being developed to evade transition metals. A great deal of work has been done on this topic in recent times and still going on. The intention of this review is to cover recent works on transition metal‐free C(sp2)−H bond halogenations on arenes as well as heteroarenes.

Nickel(II)- and Silver(I)-Catalyzed C–H Bond Halogenation of Anilides and Carbamates

Abstract ortho-C–H bond halogenation of anilides and N-aryl carbamates using easily available N-halosuccinimides (NXS) as the active halogenation reagent in the presence of nickel or silver catalyst has been developed. This method provides a new approach to 2-haloanilides and carbamates, which may serve as starting materials for the synthesis of pharmaceutically and biologically active compounds.

Photoexcited Pd(ii) auxiliaries enable light-induced control in C(sp3)-H bond functionalisation.

Herein we report the photophysical and photochemical properties of palladacycle complexes derived from 8-aminoquinoline ligands, commonly used auxiliaries in C–H activation. Spectroscopic, electrochemical and computational studies reveal that visible light irradiation induces a mixed LLCT/MLCT charge transfer providing access to synthetically relevant Pd(iii)/Pd(iv) redox couples. The Pd(ii) complex undergoes photoinduced electron transfer with alkyl halides generating C(sp3)–H halogenation products rather than C–C bond adducts. Online photochemical ESI-MS analysis implicates participation of a mononuclear Pd(iii) species which promotes C–X bond formation via a distinct Pd(iii)/Pd(iv) pathway. To demonstrate the synthetic utility, we developed a general method for inert C(sp3)–H bond bromination, chlorination and iodination with alkyl halides. This new strategy in auxiliary-directed C–H activation provides predictable and controllable access to distinct reactivity pathways proceeding via Pd(iii)/Pd(iv) redox couples induced by visible light irradiation.

Trihaloisocyanuric acids in ethanol: an eco-friendly system for the regioselective halogenation of imidazo-heteroarenes

Herein, we describe an efficient, rapid and benign protocol for the direct C(sp2)–H bond halogenation (Cl, Br, I) of 2-arylimidazo[1,2-a]pyridines using trihaloisocyanuric acids in ethanol.

Direct C-H bond halogenation and pseudohalogenation of hydrocarbons mediated by high-valent 3d metal-oxo species.

Late-stage direct functionalization of the C-H bond is synthetically desirable. Metalloenzymes having metal-oxo active sites are well known to selectively catalyze hydroxylation and halogenation reactions with high efficiency. This review highlights the recent developments in the field of direct C-H halogenation and pseudohalogenation reactions catalyzed by the functional models of metalloenzymes.

Aliphatic C-H Bond Halogenation by Iron(II)-α-Keto Acid Complexes and O2: Functional Mimicking of Nonheme Iron Halogenases.

α-Ketoglutarate-dependent nonheme halogenases catalyze the halogenation of aliphatic C-H bonds in the biosynthesis pathway of many natural products. An iron(IV)-oxo-halo species has been established as the active oxidant in the halogenation reactions. With an objective to emulate the function of the nonheme halogenases, two iron(II)-α-keto acid complexes, [(phdpa)Fe(BF)Cl] (1) and [(1,4-tpbd)Fe2(BF)2Cl2] (2) (where phdpa = N,N-bis(2-pyridylmethyl)aniline, 1,4-tpbd = N,N, N',N'-tetrakis(2-pyridylmethyl)benzene-1,4-diamine, and BF = benzoylformate), have been prepared. The iron complexes are capable of carrying out the oxidative halogenation of aliphatic C-H bonds using O2 as the terminal oxidant. Although the complexes are not selective toward C-H bond halogenation, they are the only examples of nonheme iron(II)-α-keto acid complexes mimicking the activity of nonheme halogenases. The dinuclear complex (2) exhibits enhanced reactivity toward C-H bond halogenation/hydroxylation.

Remote radical halogenation of aminoquinolines with aqueous hydrogen halide (HX) and oxone

Simple and halide-atom economical HX reagents (X = Cl, Br and I) were applied to the remote CH bond halogenation reaction of 8-aminoquinoline amides. This strategy features a broad substrate scope and good functional group tolerance. A series of C5-halogenated 8-aminoquinolines were obtained in moderate to good yields under mild conditions.

Site-selective bromination of sp3 C-H bonds.

A method for converting sp3 C-H to C-Br bonds using an N-methyl sulfamate directing group is described. The reaction employs Rh2(oct)4 and a mixture of NaBr and NaOCl and is performed in aqueous solution open to air. For all sulfamates examined, oxidation occurs with high selectivity at the γ-carbon, affording a uniquely predictable method for C-H bond halogenation. Results from a series of mechanistic experiments suggest that substrate oxidation likely proceeds by a radical chain process. Initial formation of an N-halogenated sulfamate followed by Rh-mediated homolysis generates an N-centered radical, which serves as the active oxidant.

A Convenient Strategy for Remote C–H Bond Halogenation of 8-Aminoquinolines in the C5 Position

A highly efficient and convenient strategy has been developed for remote C–H bond halogenation of 8-aminoquinolines in good to excellent yields under transition-metal-free conditions. The reaction tolerates a variety of functional groups and can potentially be scaled up.

A Base-Resistant Metalloporphyrin Metal-Organic Framework for C-H Bond Halogenation.

A base-resistant porphyrin metal-organic framework (MOF), namely PCN-602 has been constructed with 12-connected [Ni8(OH)4(H2O)2Pz12] (Pz = pyrazolate) cluster and a newly designed pyrazolate-based porphyrin ligand, 5,10,15,20-tetrakis(4-(pyrazolate-4-yl)phenyl)porphyrin under the guidance of the reticular synthesis strategy. Besides its robustness in hydroxide solution, PCN-602 also shows excellent stability in aqueous solutions of F-, CO32-, and PO43- ions. Interestingly, the Mn3+-porphyrinic PCN-602, as a recyclable MOF catalyst, presents high catalytic activity for the C-H bond halogenation reaction in a basic system, significantly outperforming its homogeneous counterpart. For the first time, a porphyrinic MOF was thus used as an efficient catalyst in a basic solution with coordinating anions, to the best of our knowledge.

Copper‐Mediated Remote Highly Site‐Selective C–H Bond Bromination and Chlorination of Quinolines at the C5 Position that is Geometrically Difficult to Access

A concise, simple, and efficient method for remote C–H bond halogenation (Br and Cl) of 8‐aminoquinoline scaffolds at the geometrically difficult‐to‐access C5 position was explored with diverse substrate combinations in DMF. This protocol made use of inexpensive CuBr2 and CuCl2 as mediators and showed good to excellent yields for as many as 24 substrate combinations. The outstanding site selectivity of the reaction was reflected by the lack of formation of the undesired C7‐halogenated byproduct originating from the high nucleophilic reactivity of the 8‐aminoquinoline scaffold at the C7 position, even if excess amounts of the CuX2 salts were used.

RhIII‐Catalyzed Directed C−H Bromination and Iodination to Synthesize Atropisomeric Biaryls

AbstractThe [RhIIICp*]‐catalyzed directed C−H bromination and iodination reactions of 2‐aryl isoquinolines/pyridines are highly efficient and afford atropisomeric biaryl compounds (Cp*=1,2,3,4,5‐pentamethylcyclopenta‐2,4‐dienyl) in good yields. Among several reported C−H bond halogenation methods, the combination of [RhIIICp*Cl2]2/AgSbF6, N‐halosuccinimide, and pivalic acid in 1,2‐dichloroethane is found to be the only effective catalytic system to provide atropisomeric 2′‐halogenated 2‐aryl isoquinolines/pyridines.

ChemInform Abstract: C—H Bond Halogenation Catalyzed or Mediated by Copper: An Overview

AbstractReview: [72 refs.

Micellar Catalysis: Bioinspired Micellar Copper Protoporphyrin as a High Performing Nano-Catalyst.

Herein we have engineered a micellar Cu protoporphyrin catalyst that mediates carbon bond activation using peroxide as an electron source. Cu protoporphyrin is a biomimetic model of active site of chloroperoxidase enzyme, which catalyzes the carbon bond halogenation in the presence of a suitable amount of H2O2. The encapsulation of Cu(II) Protoporphyrin IX/L-Cysteine inside of cetyltrimethylammonium bromide micelle increases the rate of chlorination at pH 3. The cited catalyst resists high concentrations of hydrogen peroxide, which is previously reported as a suicide inactivator component of hemo-enzymes. Isothermal Titration Calorimetry (ITC) and Dynamic Light Scattering (DLS) data have revealed the formation of a micellar complex by encapsulation of six Cu(II) proporphyrins within each micelle. Moreover, electrochemical investigations indicate that L-Cysteine increases the intensity of electron transferred due to the formation of self-assembled monolayer on Au electrode. Our results paved a road toward the design of a more robust mimetic catalysis based on Protoporphyrin IX derivatives.

Modeling Non-Heme Iron Halogenases: High-Spin Oxoiron(IV)-Halide Complexes That Halogenate C-H Bonds.

The non-heme iron halogenases CytC3 and SyrB2 catalyze C-H bond halogenation in the biosynthesis of some natural products via S = 2 oxoiron(IV)-halide intermediates. These oxidants abstract a hydrogen atom from a substrate C-H bond to generate an alkyl radical that reacts with the bound halide to form a C-X bond chemoselectively. The origin of this selectivity has been explored in biological systems but has not yet been investigated with synthetic models. Here we report the characterization of S = 2 [Fe(IV)(O)(TQA)(Cl/Br)](+) (TQA = tris(quinolyl-2-methyl)amine) complexes that can preferentially halogenate cyclohexane. These are the first synthetic oxoiron(IV)-halide complexes that serve as spectroscopic and functional models for the halogenase intermediates. Interestingly, the nascent substrate radicals generated by these synthetic complexes are not as short-lived as those obtained from heme-based oxidants and can be intercepted by O2 to prevent halogenation, supporting an emerging notion that rapid rebound may not necessarily occur in non-heme oxoiron(IV) oxidations.

C-H bond halogenation catalyzed or mediated by copper: an overview.

Carbon–halogen (C–X) bonds are amongst the most fundamental groups in organic synthesis, they are frequently and widely employed in the synthesis of numerous organic products. The generation of a C–X bond, therefore, constitutes an issue of universal interest. Herein, the research advances on the copper-catalyzed and mediated C–X (X = F, Cl, Br, I) bond formation via direct C–H bond transformation is reviewed.