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A chemodivergent protocol for the (de)hydrogenative coupling of azoarenes with benzyl alcohol is described via the NN bond activation using an inexpensive and well-defined nickel catalyst.

Direct functionalization of heterocycles is an advanced strategy for diversifying privileged and biorelevant heterocycle-containing molecules. Particularly, use of the most abundant transition metal, iron, as a catalyst makes this process highly cost-effective and sustainable. Recently, some progress has been realized towards the direct functionalization of heterocycles under iron catalysis. Herein, we present the developments in the C–H bond functionalizations and related reactions of various heterocycles by abundant iron salts. This Synpacts is categorized into different sections based on heterocycles being functionalized, and each section is discussed based on the type of reaction catalyzed by iron.1 Introduction2 Functionalization of Indoles2.1 Alkylation2.2 Alkenylation2.3 Other Reactions3 Oxindoles and Isatins3.1 C–C Bond Formation3.2 C–Heteroatom Bond Formation4 Pyridines and Furans5 Functionalization of Azoles6 Summary and Outlook

Chemoselective hydrogenation of CC, CO and CN bonds in α,β-unsaturated ketones, aldehydes and imines is accomplished at room temperature (27 °C) using a well-defined Mn(i) catalyst and 5.0 bar H2.

Room temperature chemo- and stereoselective hydrogenation of alkynes is described using a well-defined and phosphine-free hemilabile cobalt catalyst.

Chemoselective hydrogenation of C[double bond, length as m-dash]C, C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds in α,β-unsaturated ketones, aldehydes and imines is accomplished at room temperature (27 °C) using a well-defined Mn(i) catalyst and 5.0 bar H

Direct C-H functionalization of privileged and biologically relevant azoles and indoles represents an important chemical transformation in molecular science. Despite significant progress in the palladium-catalyzed regioselective C-H functionalization of azoles and indoles, the use of abundant and less expensive nickel catalyst is underdeveloped. In the recent past, the nickel-catalyzed regioselective C-H alkylation, arylation, alkenylation and alkynylation of azoles and indoles have been substantially explored, which can be applied to the complex organic molecule synthesis. In this Account, we summarize the developments in nickel-catalyzed regioselective functionalization of azoles and indoles with a considerable focus on the reaction mechanism.

Palladium-catalyzed chemoselective C(sp2)-H and C(sp3)-H acetoxylation of synthetically useful tertiary amides is reported under relatively mild reaction conditions. This protocol proceeds through the assistance of a weakly coordinated directing group (C═O) and requires low catalyst (1.0 mol %) loading. Diverse functionalities, such as C(sp2)-Cl, C(sp3)-Cl, -CF3, -COOEt, and -NO2 groups, including morpholinyl, piperazinyl, and pyrrolidinyl heterocycles, are compatible under the reaction conditions. Further functionalization of this protocol is demonstrated by hydrolysis to alcohols, alcohol-acids, as well as reduction to tertiary amines. A preliminary kinetic isotope effect study supported the rate-limiting C-H bond activation process.

C–O bond formation represents a fundamental chemical transformation in organic synthesis to develop valuably oxygenated (hetero)arenes. Particularly, the direct and regioselective C–H bond oxygenation of privileged amides, using a transition metal catalyst and a mild oxygenating source, is a step-economy and attractive approach. During the last decade, considerable progress has been realized in the direct C–H oxygenation of primary, secondary, and tertiary amides. This Short Review compiles the advances in transition-metal-catalyzed oxygenation of C(sp2)–H and C(sp3)–H bonds on various amides with diverse oxygenation sources. The review is categorized into two different major sections: (i) C(sp2)–H oxygenation and (ii) C(sp3)–H oxygenation. Each section is discussed based on the directing group (monodentate and bidentate) attached to the amide derivatives.1 Introduction2 C(sp2)–H Oxygenation2.1 Monodentate Directed2.2 Bidentate Directed3 C(sp3)–H Oxygenation3.1 Monodentate Directed3.2 Bidentate Directed4 Conclusion and Outlook

Alkylation represents an important organic transformation in molecular science to develop privileged alkylated arenes and heteroarenes. Especially, the direct C–H bond alkylation using unactivated ...

We describe the synthesis of new NNN-oxazolinyl-pincer nickel complexes and their application in the transfer hydrogenation of ketones. Achiral NNN-ligands, R′2-oxazolinyl-2-C6H4-NH-C(O)CH2NEt2 [(R′2-OxNNNEt2)–H; R’ = H (3a), R′ = Me (3b)], and chiral ligands, (R)-R′-oxazolinyl-2-C6H4-NH-C(O)CH2NEt2 [(R)-(R′-OxNNNEt2)–H; R′ = Ph (3c), R′ = CH2Ph (3d), R′ = iPr (3e), R′ = CH2iPr (3f)], were efficiently synthesized. Treatment of these ligands with (DME)NiCl2 afforded the desired amido-pincer nickel complexes, (R′2-OxNNNEt2)NiCl [R′ = H (4a), R′ = Me (4b)] and (R′-OxNNNEt2)NiCl [R′ = Ph (4c), R′ = CH2Ph (4d), R′ = iPr (4e), R′ = CH2iPr (4f)], in good yields. All the ligand precursors and nickel complexes were thoroughly characterized by various analytical techniques. The molecular structures of 4a, 4d and 4f were established by X-ray crystallography. The developed nickel complexes were found to be efficient catalysts for the transfer hydrogenation of ketones using iPrOH as a viable hydrogen source. Enantioselectivity in hydrogenation was not observed with the developed chiral catalysts.

Iron-catalyzed dimerization of various isatin derivatives is described for the efficient synthesis of 3,3'-biindolinylidene-diones (isoindigos). The reaction provides easy access to self-coupled and cross-coupled 3,3'-indolinylidene-diones that have high relevance to biology and materials. This Fe(0)- or Fe(II)-catalyzed dimerization reaction tolerates a wide range of functionalities, such as fluoro, chloro, bromo, alkenyl, nitrile, ether, ester, pyrrolyl, indolyl and carbazolyl groups, including cyclic and acyclic alkyls as well as an alkyl-bearing fatty-alcohol moiety. Especially, the coupling between two distinct isatins provided excellent selectivity for the cross-dimerization with trace of self-couplings. The single-crystal X-ray diffraction study established the molecular structure of eight dimerized products. A preliminary mechanistic study of the Fe-catalyzed dimerization supported the radical pathway for the reaction.

Selective C(sp

Regioselective C–H bond alkylation of indolines and benzo[h]quinoline with a wide range of unactivated and highly demanded primary and secondary alkyl chlorides is accomplished using a low-cost iro...

Manganese-catalyzed regioselective C–H alkylation of indoles and benzo[h]quinoline with a variety of unactivated alkyl iodides is reported. Unlike other Mn-catalyzed C–H functionalization, this pro...

Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3- R -Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug ( R )-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75-92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with ( R )- and ( S )-1-phenylethylamines, the partially enantioenriched ( R )- and ( S )-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided > 99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee , and has been reproduced in multiple batches.

Transition metal-catalysed C–H activation has emerged as an increasingly powerful platform for molecular syntheses, enabling applications to natural product syntheses, late-stage modification, pharmaceutical industries and material sciences, among others. This Primer summarizes representative best practices for the experimental set-up and data deposition for C–H activation, as well as discussing key developments including recent advances in asymmetric, photoinduced and electrocatalytic C–H activation. Likewise, strategies for applications of C–H activation towards the assembly of structurally complex (bio)polymers and drugs in academia and industry are discussed. In addition, current limitations in C–H activation and possible approaches for overcoming these shortcomings are reviewed. This Primer provides an overview of the best practices for C–H activation as well as key advances in asymmetric, photoinduced and electrocatalytic-mediated catalysis for this synthetic platform. An overview of how C–H activation facilitates the synthesis of molecules such as structurally complex (bio)polymers and drugs is provided along with the current challenges and priorities for the next decade.

Alkenylation of benzothiazoles and related azoles with alkenyl bromides is achieved employing the well-defined and air-stable nickel complexes, (bpy)NiBr2 and [Ni(bpy)3][NiBr4], as catalysts. Numerous electronically distinct alkenyl bromides efficiently coupled with substituted benzothiazoles, oxazoles, and benzimidazoles under the catalytic conditions to afford 2-alkenylated azoles. An extensive mechanistic study of the alkenylation of benzothiazole using (bpy)NiBr2 highlights a single-electron transfer process for the reaction involving the two-step one-electron oxidative addition of alkenyl bromide. The substrate benzothiazole plays a significant and diverse role in the reaction, and C–H bond cleavage is reversible in nature. Detailed kinetic analysis and control reactivity studies are indicative of a Ni(I)/Ni(III) pathway for the alkenylation comprising the rate-influencing reductive elimination step.

A mild and efficient nickel-catalyzed method for the chemo and regioselective coupling of unactivated alkyl chlorides with the C–H bond of indoles and pyrroles at 60 °C is described., A mild and efficient nickel-catalyzed method for the coupling of unactivated primary and secondary alkyl chlorides with the C–H bond of indoles and pyrroles is described which demonstrates a high level of chemo and regioselectivity. The reaction tolerates numerous functionalities, such as halide, alkenyl, alkynyl, ether, thioether, furanyl, pyrrolyl, indolyl and carbazolyl groups including acyclic and cyclic alkyls under the reaction conditions. Mechanistic investigation highlights that the alkylation proceeds through a single-electron transfer (SET) process with Ni(i)-species being the active catalyst. Overall, the alkylation follows a Ni(i)/Ni(iii) pathway involving the rate-influencing two-step single-electron oxidative addition of alkyl chlorides.

Nickel-catalyzed regioselective C–H bond alkenylation of indoles and related heteroarenes with alkenyl bromides is accomplished under relatively mild conditions. This method allows the straightforward synthesis of C-2 alkenylated indoles employing an air-stable and well-defined nickel catalyst, (bpy)NiBr2, providing a solution to the limitations associated with hydroindolation and oxidative alkenylation. The reaction conceded the coupling of indole derivatives with various alkenyl bromides, such as aromatic and heteroaromatics, α- and β-substituted as well as exo- and endo-cyclic alkenyl compounds. An extensive mechanistic investigation, including controlled study, reactivity experiments, kinetics and labeling studies, and EPR and XPS analyses, highlights that the alkenylation proceeds through a single-electron transfer process comprising an odd-electron oxidative addition of alkenyl bromide. Furthermore, the alkenylation operates via a probable Ni(I)/Ni(III) pathway involving the rate-limiting C–H nickel...

Palladium-catalyzed chemoselective C(sp

Selective hydrogenation of nitriles and alkynes is crucial considering the vast applications of reduced products in industries and in the synthesis of bioactive compounds. Particularly, the late 3d transition metal catalysts (manganese, iron, cobalt, nickel and copper) have shown promising activity for the hydrogenation of nitriles to primary amines, secondary amines and imines. Similarly, semihydrogenation of alkynes to E- and Z-alkenes by 3d metals is adequately successful both via the transfer hydrogenation and by using molecular hydrogen. The emergence of 3d transition metals in the selective synthesis of industrially relevant amines, imines and alkenes makes this protocol more attractive. Herein, we provide a concise overview on the late 3d transition metal-catalyzed hydrogenation of nitriles to amines and imines as well as semihydrogenation of alkynes to alkenes.

The nickel system (THF)2NiBr2/phen has recently been shown as an efficient catalyst for the C–H bond alkynylation of diverse heteroarenes with (triisopropylsilyl)alkynyl bromide via monodentate chelation assistance. Herein, we report an extensive mechanistic investigation for the direct alkynylation of indoles involving the well-defined nickel catalyst, which features a coordinative insertion pathway of alkynyl bromide with the Ni(II) catalyst. Catalytic relevant nickel complexes, (phen)NiCl2 (5), (phen)2NiCl2 (6) and [(phen)3Ni]·NiCl4 (7) were isolated, and the complexes 6 and 7 were structurally characterized. Well-defined complexes were as competent as the in situ generated catalyst system (THF)2NiBr2/phen for the alkynylation of indoles. Various controlled studies and reactivity experiments were performed to understand the probable pathway for the alkynylation reaction. Kinetics analysis highlights that the complex (phen)NiX2 acts as a precatalyst, and the involvement of substrate indole and LiOtBu ar...

Regioselective C(2)-H difluoroalkylation of C-3 unsubstituted indoles with commonly available fluoroalkyl bromides is successfully achieved employing a simple nickel catalyst system, (DME)NiCl2 /Xantphos. This methodology shows excellent regioselectivity and exhibits a broad substrate scope. Various functional groups, such as -OMe, -F, and -Br, are tolerated on the indole backbone to give the difluoroalkylated products in moderate to good yields. Preliminary mechanistic findings demonstrate that the reaction is homogeneous in nature and involves a radical manifold. Synthetic utility of this nickel-catalyzed method is demonstrated by synthesizing melatonin receptor antagonist Luzindole derivative.

The quinolinyl-based pincer nickel complex, κN,κN,κN-{C9H6N-(μ-N)-C6H4–NMe2}NiCl [(QNNNMe2)NiCl; (1)] has recently been demonstrated to be an efficient and robust catalyst for the alkylation of azoles with alkyl halides under copper-free conditions. Herein, we report the detailed mechanistic investigation for the alkylation of azoles catalyzed by (QNNNMe2)NiCl (1), which highlights an iodine-atom transfer (IAT) mechanism for the reaction involving a NiII/NiIII process. Deuterium labeling experiments indicate reversible cleavage of the benzothiazole C–H bond, and kinetic studies underline a fractional negative rate order with the substrate benzothiazole. The involvement of an alkyl radical during the alkylation is validated by radical clock and external additive experiments. An active intermediate species (QNNNMe2)Ni(benzothiazolyl) (5a) has been isolated and structurally characterized. The complex (QNNNMe2)Ni(benzothiazolyl) (5a) is found to be the resting state of catalyst 1. Kinetic analysis of electron...

Six-membered pincer nickelacycle complexes have been synthesized and employed for the catalytic C–H bond alkylation of benzothiazole. The pincer nickelacycle, $$\{\kappa ^{\mathrm{P}},\kappa ^{\mathrm{C}}, \kappa ^{\mathrm{P}}\hbox {-}(2\hbox {-}{}^{i}\hbox {Pr}_{2}\hbox {POCH}_{2}\hbox {-C}_{6}\hbox {H}_{3}\hbox {-}6\hbox {-CH}_{2}\hbox {OP}^{i}\hbox {Pr}_{2})\}\hbox {NiBr}$$ , $$[({}^{i}\hbox {Pr}_{4}\hbox {-POCCCOP})\hbox {NiBr}\quad (\mathbf{2})]$$ was synthesized by the reaction of 1, $$3\hbox {-}^{i}\hbox {Pr}_{2}\hbox {POCH}_{2}\hbox {-C}_{6}\hbox {H}_{4}\hbox {-CH}_{2}\hbox {OP}^{i}\hbox {Pr}_{2}$$ $$[({}^{i}\hbox {Pr}_{4}\hbox {-POCCCOP})-\hbox {H}\,\,(\mathbf{1})]$$ with $$(\hbox {CH}_{3}\hbox {CN})_{2}\hbox {NiBr}_{2}$$ in the presence of $$\hbox {Et}_{3}\hbox {N}$$ via the C(2)–H activation on ligand 1. Treatment of $$[({}^{i}\hbox {Pr}_{4}\hbox {-POCCCOP})\hbox {NiBr}]\,\,(\mathbf{2})$$ with AgOAc afforded the complex $$[({}^{i}\hbox {Pr}_{4}\hbox {-POCCCOP})\hbox {Ni}(\hbox {OAc})]$$ (3) in good yield. Both the complexes 2 and 3 were characterized by $${}^{1}\hbox {H}$$ , $${}^{13}\hbox {C}$$ and $${}^{31}\hbox {P}$$ -NMR spectral analysis. Further, the molecular structures of complexes 2 and 3 were established by X-ray crystallography. The complex 2 was found to be an active catalyst for the C–H bond alkylation of benzothiazole with alkyl halides containing $$\beta $$ –hydrogen atoms. Synopsis. Six-membered pincer nickelacycles have been synthesized and structurally characterized, which show catalytic activity for the C–H bond alkylation of benzothiazole with alkyl halides containing $$\beta $$ –hydrogen atoms.

Nickel-catalyzed oxidative C(sp2)–H/C(sp3)–H coupling of indoles with toluene derivatives is successfully achieved in the presence of 2-iodobutane as the oxidant. This method allows the selective C-2 benzylation of indoles with toluene derivatives over the alkylation with 2-iodobutane and permits the coupling of diversified indoles via the monochelation assistance. The reaction proceeded through a single-electron-transfer (SET) process, wherein both the C–H nickelation of indole and the C–H activation of toluene derivatives have a significant effect on the entire reaction rate. The synthetic utility of this nickel-catalyzed protocol is demonstrated by the facile removal of the directing group and by the convenient synthesis of the melatonin receptor antagonist Luzindole derivatives.

An efficient solvent-free nickel-catalyzed method for C-H bond arylation of arenes and indoles has been developed, which proceeds expeditiously through chelation assistance. The reaction is highly selective for mono-arylation and tolerates sensitive and structurally diverse functionalities, such as halides, ethers, amines, indole, pyrrole and carbazole. This reaction represents the first example of a nickel-catalyzed C-H arylation by monochelate assistance and symbolizes a rare precedent in solvent-free C-H arylation. Mechanistic investigations by various controlled reactions, kinetic studies, and deuterium labeling experiments suggest that the arylation follows a single electron transfer (SET) pathway involving the turnover-limiting C-H nickelation process.

(Quinolinyl)amido-ligated palladium(II) complexes have been synthesized and applied in the catalytic C–H bond arylation of benzothiazoles. The tridentate ligand precursors R2N-C(O)CH2-(NH)-C9H6N [(R2NNN8-Q)–H; R2N = morpholinyl, Me-N-piperazinyl] and the pincer palladium complexes [κN,κN,κN-{R2N-C(O)CH2-(μ-N)-C9H6N}]PdX [(R2NNN8-Q)PdX {R2N = Et2N, morpholinyl, Me-N-piperazinyl; X = OAc or Cl}] were efficiently synthesized, and characterized by various analytical techniques. The iodo derivative (Et2NNN8-Q)PdI was obtained in excellent yield by the treatment of the complex (Et2NNN8-Q)PdCl with KI. The molecular structures of complexes (Et2NNN8-Q)Pd(OAc) (2a), (Et2NNN8-Q)PdCl (3a) and (Et2NNN8-Q)PdI (4a) were elucidated by X-ray crystallography. Complex 3a was found to be the most efficient catalyst for direct C–H bond arylation of substituted benzothiazoles with diverse aryl iodides using a mild base, K2CO3. The working catalyst system 3a is highly robust and can be recycled and reused several times for the arylation of benzothiazole without loss of catalytic activity. Preliminary mechanistic investigations using controlled studies and kinetic analysis have been performed, which greatly support a molecular mechanism for the arylation.

This chapter describes the chemistry of phosphine-ether and phosphine-thioether ligated copper(I) complexes. The synthesis and characterization of some of these complexes are discussed, including the X-ray structure description. Particularly, the photophysical properties of copper(I) complexes have been highlighted in detail. Some of the copper(I) complexes show excellent photoluminescence property and are comparable with the noble metal counterpart. Catalytic activity of copper(I) complexes ligated with phosphine-ether and phosphine-thioether has been discussed in detail.

Chiral palladacycle complexes as a catalyst in asymmetric transformation are rapidly expanding. This chapter mainly focuses on the application of chiral palladacycles as a catalyst or as a catalytic intermediate in enantioselective chemical transformations. In particular, enantioselective arylation and allylic alkylation leading to the formation of new asymmetric centers are highlighted. Enantioselective [3,3]-sigmatropic rearrangement reaction catalyzed by novel chiral palladacycle is elaborated in detail. Additionally, asymmetric hydrophosphination of alkenes to generate chiral tertiary phosphines and other important phosphines is described. Most of these asymmetric transformations by the palladacycle catalyst are accompanied by excellent yields and high enantioselectivities.

A nickel-catalyzed direct C-2 alkylation of indoles through monodentate-chelation assistance has been described. This reaction proceeds via an unusual strategy by the use of a well-designed and defined (quinolinyl)amido–nickel catalyst, [{κN,κN,κN-Et2NCH2C(O)(μ-N)C9H6N}Ni(OAc)], providing a solution to the limitations associated with bidentate-chelate auxiliaries. The method allows coupling of indoles with various unactivated primary and secondary alkyl halides with ample substrate scope. This uniquely strategized alkylation proceeded through crucial C–H activation and via an alkyl radical intermediate. The reaction by this approach represents a rare example of Ni-catalyzed monodentate-chelate-assisted C–H functionalization.

The quinoline-based pincer nickel(II) complexes κN,κN,κN-{R2N-C6H4-(μ-N)-C9H6N}NiX ((R2NNNQ)NiCl: R = Me, 2a; R = Et, 2b) were synthesized by the reaction of the ligand precursors (R2NNNQ)H (R = Me, 1a; R = Et, 1b) with (DME)NiCl2 in the presence of Et3N. Similarly, the pincer nickel(II) derivatives (R2NNNQ)NiX (R = Me, X = Br, 3a; R = Et, X = Br, 3b; R = Me, X = OAc, 4a) were obtained by treatment of the ligands (R2NNNQ)H with the nickel precursor (THF)2NiBr2 or Ni(OAc)2. All of these complexes were characterized by 1H and 13C NMR spectroscopy as well as by elemental analysis. Further, the molecular structures of 2a and 3a,b were elucidated by X-ray crystallography. Complex 2a is found to be an efficient catalyst for the direct C–H bond alkylation of substituted benzothiazoles and oxazoles with various unactivated alkyl halides containing β-hydrogens under mild reaction conditions. The catalyst 2a is very robust and was recycled and reused five times for the alkylation reaction without a decrease in its ...

Pincer-based (R2POCNR′2)PdCl complexes along with CuI cocatalyst catalyze the arylation of azoles with aryl iodides to give the 2-arylated azole products. Herein, we report an extensive mechanistic investigation for the direct arylation of azoles involving a well-defined and highly efficient (iPr2POCNEt2)PdCl (2a) catalyst, which emphasizes a rare PdII–PdIV–PdII redox catalytic pathway. Kinetic studies and deuterium labeling experiments indicate that the C–H bond cleavage on azoles occurs via two distinct routes in a reversible manner. Controlled reactivity of the catalyst 2a underlines the iodo derivative (iPr2POCNEt2)PdI (3a) to be the resting state of the catalyst. The intermediate species (iPr2POCNEt2)Pd-benzothiazolyl (4a) has been isolated and structurally characterized. A determination of reaction rates of compound 4a with electronically different aryl iodides has revealed the kinetic significance of the oxidative addition of the C(sp2)–X electrophile, aryl iodide, to complex 4a. Furthermore, the r...

Quinolinamide-based pincer copper(II) complexes, κN,κN,κN-{C9H6N-(μ-N)-C(O)CH2NEt2}CuX [(QNNNEt2)CuX (X = Cl, 2; X = Br, 3; X = OAc, 4)], were synthesized by the reaction of ligand (QNNNEt2)-H (1) with CuX2 (X = Cl, Br or OAc) in the presence of Et3N. The reaction of (QNNNEt2)-H with CuX (X = Cl, Br or OAc) also afforded the Cu(II) complexes 2, 3 and 4, respectively, instead of the expected Cu(I) pincer complexes. The formation of Cu(II) complexes from Cu(I) precursors most likely occurred via the disproportionation reaction of Cu(I) into Cu(0) and Cu(II). A cationic complex [(QNNNEt2)Cu(CH3CN)]OTf (5) was synthesized by the treatment of neutral complex 2 with AgOTf. On the other hand, the reaction of (QNNNEt2)-H (1) with [Cu(MeCN)4]ClO4 produced cationic Cu(I) complex, [(QNN(H)NEt2)Cu(CH3CN)]ClO4 (6), in good yield. All complexes 2–5 were characterized by elemental analysis and HRMS measurements. Furthermore, the molecular structures of 2, 3 and 4 were elucidated by X-ray crystallography. Complex 4 crystallizes in a dimeric and catemeric pattern. The cationic complex 5 was found to be an efficient catalyst for the Kumada coupling reaction of diverse nonactivated alkyl chlorides and bromides with alkyl magnesium chloride under mild reaction conditions.

A metal-free method for the regioselective C-3 acetoxylation of the N-substituted indoles with PhI(OAc)2 is described under mild reaction conditions. This method tolerates a broad range of functional groups with moderate to good yields. The π-electron-deficient aryl-substituents on the N-atom of indoles and the acidic reaction medium remarkably favor C-3 acetoxylation.

Regioselective C–H bond palladation of the hybrid pincer-type ligands, 3-R2PO-C6H4-1-CH2NiPr2 [R2POCNiPr2–H; R = Ph (1a), R = Et2N (1b)] has been described to accomplish mono- and binuclear palladacycles. The reactions of the ligands R2POCNiPr2–H (1a, 1b) with Pd(COD)Cl2 in the presence of K3PO4 afforded the mononuclear pincer complexes {κP,κC,κN-2-(R2PO)-C6H3-6-(CH2NiPr2)}PdCl (R2POCNiPr2)PdCl [R = Ph (2a), R = Et2N (2b)], whereas similar reactions in the presence of Et3N produced the chloro-bridged binuclear palladacycles [{κP,κC-2-(R2PO)-C6H3-4-(CH2NiPr2)}(μ-Cl)Pd]2 {R = Ph (4a), R = Et2N (4b)} via the regioselective ligands C(2)–H and C(4)–H bond activation, respectively. Similarly, the reaction of a previously reported ligand iPr2POCNiPr2–H (1c) with Pd(COD)Cl2 in the presence of Et3N affords a chloro-bridged binuclear complex [{κP,κC-2-(iPr2PO)-C6H3-4-(CH2NiPr2)}(μ-Cl)Pd]2 (4c) via the regioselective C(4)–H bond palladation. On the contrary, using Pd(OAc)2 instead of Pd(COD)Cl2 in the palladation reaction of 1a, in the presence or absence of base, leads to the exclusive formation of the acetate-bridged binuclear palladacycle [{κP,κC-2-(Ph2PO)-C6H3-4-(CH2NiPr2)}(μ-OAc)Pd]2 (5a). Mechanistic detail for this regioselective C–H bond activation to achieve mono- and binuclear palladacycles has been demonstrated, which highlights that the coordinating ability of the external base, sterics between the coordinated base and N-arm of the POCN ligand as well as the electrophilicity of the palladium center are crucial to the regioselective palladation. The palladium complex 4c was shown to be the active catalyst for the direct arylation of azoles with aryl iodides under mild reaction conditions.

Application of palladacycle complexes in catalytic organic transformation is rapidly expanding. This chapter is mainly focused on the use of palladacycle precatalysts in C H bond functionalizations, as well as an overview of palladacycle intermediates in directed C H bond functionalization reactions. The described palladacycle precatalysts are more efficient and more selective than the traditional palladium complexes for C H bond functionalization processes. The second part of the chapter summarizes the involvement of palladacycle intermediates in various directed C H bond functionalizations that are proposed with experimental evidence. Some of the palladacycle intermediates described are shown to be competent as catalyst precursors. It has been demonstrated that the formation of palladacycle (precatalyst or intermediate) makes the C H functionalization process more facile, because of the high stability associated with palladacycles.