Bn benzyl n-Bu n-butyl t-Bu tert-butyl calcd. calculated cat. catalytic CMD concerted metalation-deprotonation COSY correlated spectroscopy Cy Cyclohexyl d doublet δ chemical shift DCE 1,2-Dichloroethane DFT density function theory DG directing group Scheme 1.1: Palladium-catalyzed cross-coupling reactions. With respect to ecological and economical aspects of organic synthesis, new concepts for more sustainable transition metal-catalyzed direct C-H functionalizations have been conceived. [13,

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... ] e direct C-H functionalization has the advantage that the prefunctionalization of the starting materials is not required, which is accompanied with a significant reduction of waste material 4. The Scheme 1.2 shows the three different strategies that are widely used for the transformations in transition metal-catalyzed direct C-H functionalizations. [15] The direct cleavage of C-H bonds and their transformation into C-Het bonds has become a compelling research area in modern chemistry geared to achieving complex target structures. These protocols offer appealingly short routes to natural products, pharmaceuticals, and agrochemicals. Scheme 1.2: Strategies for the transition metal-catalyzed direct C-H functionalizations. In analogy to traditional cross-coupling chemistry, Scheme 1.2a shows the coupling between 5 with an unactivated C-H bond and an aryl-or vinyl(pseudo)halide and halides 6. The reaction demonstrated in (Scheme 1.2b) works inversely: The C-H bond in an aryl-or vinyl-substrate is functionalized with an organometallic reagent 7. For these kind of reactions, however, the use of an oxidant is mandatory. The Scheme 1.2c describes the dehydrogenative coupling between substrates 5 through activation of two C-H bonds and the formal generation of dihydrogen. However, an oxidant is also needed for this type of reactions. Although a number of transformations in which a C-H bond is functionalized with participation of a transition metal-activated ligand via a transition metal-induced radical-chain mechanism are known, Shilov classifies only specific types of reactions as "true C-H activation". [16] In these reactions, the metal is directly involved in the cleavage of the C-H bond and a M-C -bond is formed. 9] [20] Scheme 1.3: Different mechanisms for transition metal-catalyzed C-H activation. The first pathway shown in Scheme 1.3a is the oxidative addition of a C-H bond to the metal center. This process can occur for electron-rich and low-valent late transition metals, such as rhenium, iron, ruthenium, osmium, iridium and platinum. If late-or post-transition metals are employed in high oxidation stages, including palladium(II), platinum(II), platinum(IV), mercury(II), the mechanism is frequently shifted towards an electrophilic substitution (Scheme 1.3b). However, early group 3 and 4 transition metals as well as lanthanides cannot undergo oxidative addition. For these metals -bond metathesis (SBM) usually takes place (Scheme 1.3c). C-H activation can also proceed via 1,2-addition to unsaturated Π=X bonds (Scheme 1.3d). As a novel mode of action, an increasing mode of C-H activation, many of reactions proceeds via "base-assisted" C-H activation. [19] For instance, a carboxylate-ligand on the transition metal can act as base to promote the abstraction of the proton, along with an possible. This transition state appears to be a SBM (Scheme 1.3c). However, calculations by Goddard III et al. revealed that, in contrast to SBM, the M-O bond is based on a different orbital than the newly formed H-O bond. [25, 26] Herein, a four-membered transition state was proposed and mechanistic pathway is termed as "internal electrophilic substitution" (IES) [26] . In this context, theoretical calculations have offered new insight into the mechanism of baseassisted C-H metalation. Based on computational studies, Davies and Macgregor described Site-Selectivity and Directing Groups in C-H Bond Functionalization The main challenge in C-H activation chemistry is the chemo-and site-selective cleavage of specific C-H bonds. The selective conversion of methane to methanol, for instance, is of great importance with respect to the potential use of methanol as a fuel. [27] However, the chemoselective oxidation of alkanes is still a challenging task, as alcohols and aldehydes tend to be more reactive than the hydrocarbons themselves thus resulting in overoxidation. Radicalbased reactions, on the other side, are often not selective enough and lead to product mixtures. Scheme 1.5a shows the early catalytic system which was developed by Shilov for the selective methane activation. [16] -H bonds are ubiquitous in nature, a feature which on the one hand facilitates their usage as starting material for elaboration of more complex structures. However, on the other hand, this makes controlling the site-selectivity of C-H functionalization a great challenge. In electrophilic aromatic substitution, it has been well established that electron-donating substituents direct incoming electrophiles to the ortho-(17b) and para-positions (17c), whereas electron-withdrawing substituents lead to the meta-position (17a) (Scheme 1.8). Scheme 1.8: Site-selectivity in electrophilic aromatic substitution. Based on pioneering work by Lewis, [37] in 1993 Murai et al. described the first example of a directed catalytic C-H bond functionalization of aromatic ketones 20 (Scheme 1.9). This reaction can also be considered as a hydroarylation of olefin 21. Scheme 1.8a: Hydroarylation by Lewis. Herein the carbonyl-functionality served as the directing group for the ruthenium-catalyst. 0][41] [42] [43] Scheme 1.9: Hydroarylation by Murai. Ruthenium-Catalyzed Direct Arylations with Organometallic Reagents A ruthenium-catalyzed [41b] chelation-assisted approach was developed based on the use of arylboronates [41c] as arylating agents. [41] Thereby, a regioselective ruthenium-catalyzed arylation of substrates bearing an oxygen-containing directing group was achieved. A variety of aromatic ketones were efficiently arylated in pinacolone using aryl boronates 25 with both electron-donating, as well as electron-withdrawing substituents (Scheme 1.10). Scheme 1.10. Ruthenium-catalyzed arylation of ketone in pinacolone. Mechanistic studies revealed that pinacolone acts here not only as the solvent, but also as an oxidizing agent. Additionally, inter-and intramolecular competition experiments with deuterium-labeled ketones provided evidence for a pre-coordination of the ruthenium catalyst by the oxygen of the aryl ketone. [ 41d] Thus, a mechanism was elaborated consisting of (a) coordination, (b) oxidative addition to yield an ortho-metalated ruthenacycle, (c) insertion of pinacolone into the [Ru]-H bond, (d) transmetalation, and finally (e) reductive elimination (Scheme 1.11). [ 41e] Scheme 1.11. Proposed mechanism for ruthenium-catalyzed arylations of ketones 24. An extension of this reaction to the functionalization of C(sp 3 )-H bonds was more recently reported. Thus, pyrrolidines 35 were efficiently arylated with substituted arylboronates in pinacolone, yielding, however, often mixtures of diastereomers (Scheme 1.12). [ 41f] Scheme 1.12. Ruthenium-catalyzed functionalization of a C(sp 3 )-H bond in pyrrolidine 35. Jun and coworkers used a related approach for a ruthenium-catalyzed arylation of aldimines. [ 41g] Here, a pyridyl-substituent allowed for the selective arylation with arylboronates 39. Methyl vinyl ketone (40) as additive led to high isolated yields of the corresponding ketones (Scheme 1.13). Scheme 1.13. Ruthenium-catalyzed direct arylation of aldimine 38. A catalytic system comprising [RuCl2( 6 -C6H6)]2 and PPh3 was developed by Oi, Inoue and coworkers for direct arylations of pyridine derivatives using aryl bromides as the electrophiles in NMP as the solvent (Scheme 1.14). [ 41h] Scheme 1.14. Ruthenium-catalyzed direct arylation of pyridine 43 with bromide 4. The same protocol proved applicable to directed arylations of imines, imidazolines and oxazolines as pronucleophilic starting materials in NMP (Scheme 1.15). [ 41i] Transformations of the later substrates should prove useful, since 2-oxazolinyl substituents 46 can be easily converted into a variety of valuable functionalities. [ 41j] Scheme 1.15. Ruthenium-catalyzed direct arylation with heteroaryl bromide 47. Also alkenyl C-H bonds were directly functionalyzed with aryl bromides 47 using this catalytic system in NMP, yielding regio-and stereoselectively functionalized alkenes (Scheme 1.16). [ 41k] Scheme 1.16. Ruthenium-catalyzed direct arylation of alkene 49. A phosphine ligand-free ruthenium-catalyzed direct arylation with aryl bromides as electrophiles 4 was disclosed. Notably, the use of inexpensive RuCl3•(H2O)n as catalyst allowed for economically attractive C-H functionalizations of pyridine 43, oxazoline 46 and pyrazole 51 derivatives, also with more sterically hindered ortho-substituted aryl bromides (Scheme 1.15). [ 41l,41m] Scheme 1.17. Ruthenium-catalyzed phosphine free direct arylation of pyridine 43. Among aryl halides, chlorides are the most useful simple class of electrophilic substrates, due to their lower cost and wide diversity of commercially available compounds. [41] The direct arylations with aryl chlorides were until recently only generally applicable in palladiumcatalyzed intramolecular transformations. [ 41n] However, a broadly applicable Intermolecular C-H arylation of various arenes with aryl chlorides was accomplished by Ackermann with a ruthenium complex derived from secondary phosphine oxide (SPO) (1-Ad)2P(O)H as preligand (Scheme 1.18). [ 41o] Thereby, pyridine and ketimine derivatives were efficiently C-H arylated with functionalized electron-deficient, and electron-rich, thus for an oxidative addition electronically deactivated, aryl chlorides. Scheme 1.18. Ruthenium-catalyzed direct arylation with aryl chlorides 54 and 55. Importantly, tosylates 61 are more stable towards hydrolysis than triflates. Thus, protocols for traditional cross-coupling reactions were developed by the group of Ackermann using ruthenium complex derived from heteroatom-substituted secondary phosphine oxide (HASPO) preligand 59 [41p] allowed for C-H arylations with various tosylates 58. [ 41q] . Selective mono-or diarylation reactions could be achieved through the judicious choice of the corresponding electrophile (Scheme 1.19). Thus, while aryl chlorides 60 gave rise to diarylated products, the use of aryl tosylates 61 cleanly afforded the corresponding monoarylated derivatives. Scheme 1.19. Selective ruthenium-catalyzed direct arylations through choice of electrophile. Direct arylations of pronucleophiles with inexpensive aryl chlorides 60 proceeded with high efficacy and excellent diastereoselectivity using either ruthenium carbenes or a ruthenium complex derived from air-stable secondary phosphine oxide preligand (1-Ad)2P(O)H as catalyst (Scheme 1.19). [ 41r] Transition Metal-Catalyzed Oxidative C-H functionalization with Alkenes and Alkynes Transition Metal-Catalyzed Oxidative C-H Alkenylation Palladium-catalyzed oxidative cross-coupling reactions were discovered by Fujiwara and Moritani in the late 1960s. [44] Recent years have witnessed its wide application in the preparation of numerous synthetically and practically useful heterocycles, such as isoquinolines, isoquinolones, isocoumarins, -pyrones and 2-pyridines. [47] In 1979, Hong et al. reported rhodium-catalyzed styrene synthesis using simple arenes and ethylene in the presence of CO. [48] In 2007, Satoh and Miura reported the rhodium-catalyzed oxidative alkenylation of easily accessible benzoic acid using acrylates, acryl amides or nitriles as alkenylating reagent. The oxidant was stoichiometric amounts of Cu(OAc)2•H2O in the presence of catalytic Cu(OAc)2•H2O. [49] Later, Glorius and coworkers reported the rhodium-catalyzed alkenylations of acetanilides, [50] acetophenones and benzamides. [51] In contrast, Ackermann reported independently C-H alkenylation of acetanilide 69, benzamide 70, carbamates 71, and sulfonic acid derivatives 72 (Scheme 1.20) with inexpensive ruthenium(II) catalysts. [ 51b-51e,174] Scheme 1.20: Selected examples of ruthenium(II)-catalyzed oxidative alkenylations. Transition Metal-Catalyzed Oxidative Alkyne Annulation Larock et al. in 1991 reported the efficient palladium-catalyzed alkyne annulation with substituted haloarenes. [52] Thus, a number of synthetically valuable protocols have been developed based on the Larock-type heterocyle synthesis (Scheme 1.21) [53] 81, phosphates 83 and sulfoximines 84. [ 57a-57c] Scheme 1.22: Selected examples of ruthenium(II)-catalyzed oxidative annulations. Transition Metal-Catalyzed Alkenylation and Alkyne Annulation by C-H/N-O Cleavage To the development of oxidative alkenylation and alkyne annulations subsequently utilized C-H/N-O cleavages. The advantage of this method is that the substrate itself acts as an 'internal oxidant' via N-O cleavage. Thus external oxidants such as Cu(OAc)2•H2O are no longer needed. Fagnou and coworkers initiated the rhodium(III)-catalyzed C-H alkyne annulation with hydroxamic acid esters substrates. Later, the Fagnou group as well as the Glorius group accomplished the rhodium(III)-catalyzed direct C-H olefinations of benzhydroxamic acid Oximes 88 proved to be effective internal oxidants. In 2012, Ackermann and co-workers reported the first cationic ruthenium(II) catalysts for alkyne annulations with oximes through C-H/N-O clevages (Scheme 1.23). cheme 1.23: Ruthenium(II)-catalyzed annulation by C-H/N-O bond functionalization. Transition Metal-Catalyzed C-O Formations by C-H Activation Oxygenated aromatic molecules are key intermediates in organic synthesis and important structural components of useful pharmaceuticals, agrochemicals, polymers, and biologically active compounds. [62] For instance, phenol is a central commodity chemical in industry, which is largely produced in a three step synthesis (cumene process) starting from benzene and propylene. Although during recent years transition metal-catalyzed coupling of halogenated or boronated arenes (91) to phenol (92) have been discovered, [63] [64] [65] direct C-H oxygenation should be the optimal choice considering the atom-economy aspect of oxygenation reactions and its importance in further transformations in organic synthesis (Scheme 1.24). Scheme 1.24: Selected examples of metal-mediated phenol synthesis 92. Jintoku and Fujiwara in the early 1990's, reported the palladium-catalyzed transformation of benzene ( 93 ) and molecular oxygen to phenol 92 (Scheme 1.24). [66] The palladium precursor was modified by the addition of 1,10-phenanthroline and dissolved in a mixture of benzene and acetic acid. The reaction proceeded at 180 °C under an atmosphere of oxygen (15 atm) and carbon monoxide (15 atm). The acetylated phenol (95) was monitored as a side product. Early examples of palladium-catalyzed ligand-directed C(sp 2 )-H bond oxygenation were reported by Crabtree and Sanford using PhI(OAc)2 as the stoichiometric oxidant (Scheme 1.25). [67, 174] A variety of pyridine derivatives (96) and other well decorated nitrogen-based substituents served as excellent DG, delivering ortho-acetoxylated products (97) in excellent yields. However, simple ketones and aldehydes did not undergo ortho-acetoxylation under these conditions, presumably because these are weakly-coordinating ligands for palladium. Moreover, PhI(OAc)2 could also be utilized in palladium-catalyzed ligand-directed C(sp 3 )-H bond oxygenation. [68] heme 1.25: Palladium-catalyzed C(sp 2 )-H bond oxygenation. Based on their mechanistic studies, [71, 72] Sanford and coworkers proposed the catalytic cycle for palladium-catalyzed ortho-acetoxylation as shown in Scheme 1.26. First, ligand-directed C-H activation generates a cyclopalladated intermediate 98. Second, two-electron oxidation of the palladacycle generates the palladium(IV) species 99. Third, reductive elimination releases the product 100 and regenerates the palladium(II) catalyst. [73, 74] cheme 1.26: Proposed mechanism for palladium-catalyzed ortho-acetoxylation 100. Oxgenations reactions have been studied thoroughly using inorganic peroxides, such as Oxone and K2S2O8. [71] Yet, molecular oxygen is the optimal oxygen source considering the atomeconomy aspect. Recently, the group of Yu described a palladium(II)-based catalytic system that fetched the regioselective ortho-hydroxylation of potassium benzoates with the environmentally friendly molecular oxygen as the oxidant (Scheme 1.27). [73] The reaction rates were significantly increased in presence of stoichiometric benzoquinone (BQ) and thereby converted substrates (101) into desired ortho-hydroxylated product 102 in satisfying yield with atmospheric O2. They confirmed that the oxygen-atom incorporated with labeling experiments. into the hydroxylated product originated from molecular oxygen 18 O2. Scheme 1.27: Palladium-catalyzed C(sp 2 )-H bond oxygenation. Recently, ruthenium-catalyzed hydroxylations of C-H bonds have been developed. Du Bois and coworkers disclosed the C(sp 3 )-H hydroxylation with catalytic RuCl3•nH2O using KBrO3 as the stoichiometric oxidant, allowing the oxygenation of the weakest C-H bonds in substrates 103 (Scheme1.28). [76] Thus, this method is largely limited to tertiary alkyl C-H bonds. Scheme 1.28: Ruthenium-catalyzed C(sp 3 )-H bond oxygenation. During the past few years a tremendous development in the ruthenium-catalyzed direct hydroxylation of stronger C(sp 2 )-H bonds in (hetro)arenes has been witnessed. [62] Rao and coworkers disclosed ruthenium-catalyzed ortho-hydroxylation with benzoic acid using K2S2O8 or HIO3 as the oxidant, [77] while Ackermann and coworkers employed the well-defined ruthenium(II)-biscarboxylate complex [Ru(O2CMes)2(p-cymene)] as well as inexpensive RuCl3•nH2O in the hydroxylation reactions using hypervalent iodine reagents as the oxidant. [78] While previous studies had focused on arenes bearing electronwithdrawing directing groups, the group of Ackermann [81] independently explored rutheniumcatalyzed carbamate 111 as well as weakly co-ordinating aldehyde 113 ortho-hydroxylation with excellent site-selectivities. This mode of reaction could be used in further post-synthetic functionalizations of electron-rich phenol 111 and aldehyde 113 to respective valuable heterocycles (Scheme. 1.29). [82] cheme 1.29: Selected examples of Ruthenium(II)-catalyzed C(sp 2 )-H bond hydroxylation. Whilst previous studies on ruthenium(II)-catalyzed C(sp 2 )-H bond oxygenation of arenes bearing electron-withdrawing or electron-donating directing groups are limited to acetoxylation and hydroxylations of aromatics [78] [79] [80] [81] the group of Sanford reported benzoxylation of 2-phenylpyridines with benzoate iodonium salts in the presence of a palladium catalyst. [83] In 2009, Cheng's group demonstrated benzoxylation of 2-phenylpyridines with benzoic acids in the presence of a rhodium catalyst. [84] A very recent report from the group of Jeganmohan showed the use of aryl-carboxylic acids 101 in ruthenium(II) catalysis to achieve the aryloxylation [87] of acetanilides 113 using inorganic oxidants (Scheme 1.30). [88] Transition Metal-Catalyzed C-N Bond Formations Aromatic amines are of significant importance owing to their widespread existence in natural products and artificial organic compounds. [89, 90] 95] [96] [97] As many efforts have been devoted to their synthesis, substantial achievements have been made over the past decades, and a large amount of different catalytic systems have been successfully established. The Ullmann-Goldberg condensation 121, [97] [98] [99] [100] [101] Chan-Lam coupling 124, [102] [103] [104] [105] [106] and Buchwald-Hartwig amination 124, [107] [108] [109] [110] [111] reactions are among the classic methodologies, which provide increasingly viable and practical tools for C-N bond formation (Scheme1.31). However, in all these cases, prefunctionalization of the arenes, such as for aryl halides, pseudo halides (4), or boronic acids ( 122 ) is necessary and the accompanying generation of undesired stoichiometric byproducts (hydrogen halides or the corresponding salts) cannot be avoided. Nowadays, with economic and environmental considerations becoming increasingly important, it is highly desirable to explore new strategies to circumvent those inherent limitations. Scheme 1.31: Early examples of metal-catalyzed C(sp 2 )-H bond amination. Transition-metal-catalyzed direct C-H functionalization opens a new avenue for diverse C-N bond construction in a step and atom-economical way, without the requirement of prefunctionalization of the C-H coupling partners. With the assistance of various directing groups with different coordination abilities, the cyclometalation of numerous transition-metal catalysts can regioselectively occur on the ortho-position through the C-H activation process. Subsequently, a variety of amino sources have been successfully employed as effective coupling partners to install a nitrogen-containing functional group. In general, there are two approaches to fulfill the transformation. The first employs simple neutral amines, amides, or sulfonamides as effective aminating reagents. In this process, external oxidants are always required to facilitate the formation of the C-N bond. The second strategy utilizes preactivated amino sources, including N-chloroamine, N-hydroxycarbamate, O-acylhydroxylamine, nitrosobenzene, N-fluorobenzenesulfonimide (NFSI), azides, and 1,4,2-dioxazol-5-one, under [114] [115] [116] [117] [118] Scheme 1.32: Directing group assisted ortho-C-H amination. A more detailed mechanistic consideration is illustrated in Scheme 1.32a. Starting from the reactive metallacycle species 126, a variety of amidating reagents can coordinate to the metal center to form 128a, 128b, or 128c. Several classical amidating reagents were selected to describe the following different catalytic cycles. In general, there are two kinds of possible key intermediates involved in the above amidation process. One is a nitrene intermediate whereas the other is an imido intermediate. For the first case, organic azide and 1,4,2-dioxazol-5-one are the most widely used amino source, which release compound 128bb, although some primary amines could also deliver the nitrene intermediate 128ba, which subsequently proceeded through a stepwise nitrenoid transfer pathway to yield product 127 from 128ba. For the second type, some secondary amines in the presence of external oxidant and base could generate 128bc by direct metalation. The oxidative addition of secondary N-benzoate alkylamine to the metal center followed by reductive elimination yields 127. Finally, protonolysis by another molecule of the starting material 125 or acid would afford the final aminated product 127 and regenerate the reactive species 126. Scheme 1.33: Selected examples of copper mediated C-H amination. In 2006, Yu's group rendered the stoichiometric direct C-H amination of 2-phenylpyridine (43) with amine (130). [119] One equivalent of copper(II) _ acetate was used as the catalyst and air acted as the oxidant (Scheme 1.33). However, in this preliminary work, only one example was provided without any substrate scope exploration. Later, a similar system was demonstrated by Chatani, albeit with lower efficiency. [120] Subsequently, several other groups developed different catalytic systems independently. Four years later, Li and co-workers developed an amidation of 2-arylpyridine derivatives 43 with amides by using a catalytic amount of CuBr in combination with tert-butyl peroxide (TBP) as the oxidant under neat conditions. This is a ligand and base-free transformation. [121] Satisfying yields were achieved for the secondary amides. However, when primary amides or TsNH2 were utilized, comparatively lower yields were obtained. Simultaneously, Nicholas' group reported that a catalytic amount of Cu(OAc)2 150 °C is the main limitation of this strategy. The Bolm group disclosed a rapid access to Narylated sulfoximines by copper-mediated C-H amination of 2-arylpyridines with sulfoximines. A stoichiometric amount of copper salt was required to ensure the efficiency when oxygen was used as the oxidant. [124] . Very recently, Li, Chen and coworkers presented a copper(I)bromide-catalyzed intermolecular dehydrogenative amidation of arenes with amides by using air as the terminal oxidant. A wide range of amides such as N-aryl amides, N-alkyl amides, benzamide derivatives, imides, and lactams all proved to be good coupling partners. [125] heme 1.34: Selected examples of rhodium(III) _ catalyzed C-H bond amination. Besides free amines which were explored using copper catalysts [119] [120] [121] [122] [123] [124] [125] N-chloroamine 143, [119] [120] N-aroyloxyamide 142 are another kind of efficient preactivated amino source. In 2013, the Glorius group reported a rhodium(III)-catalyzed C-H amidation using electron-deficient aroyloxycarbamates 139 as an efficient electrophilic nitrogen source (Scheme 1.34). [126] Both pyridine 43 and O-methyl hydroxamic acids served as efficient directing groups to give access to N-carbamate protected arylamines 140 under mild reaction conditions. The group of Yi, Xu and co-workers extended this type of preactivated amino reagent to include N- (2,4,6trichlorobenzoyloxy)amides, which proved to be effective coupling partners for the rhodium(III) _ catalyzed direct regioselective C2-amidation of indoles bearing an N-2-pyrimidyl directing group 146. [127] heme 1.35: Selected examples of rhodium(III) _ catalyzed C-H bond amination. The group of Chang disclosed the amidation of 2-phenylpyridine (43) with tosyl azide 149 (TsN3) which was efficiently catalyzed by a cationic Cp*Rh(III) _ species and which was generated in situ by treating [RhCp*Cl2]2 with a silver salt (Scheme 1.35). [128] Besides pyridine 43, quinoline 135, pyrazole 51, and oxime 117 as well as purine 160 could also be used as good chelation groups to promote the amidation with moderate to good yields. In addition, the reaction could be scaled up. [129] Since then, TsN3 149 has become a popular amidating reagent for various amidation processes. For instance, Zhou, Li et al. developed a rhodium-catalyzed direct C2-amidation of indoles bearing a 2-pyrimidyl unit as a directing group through C-H activation by using sulfonyl azides 149-153 as the amine source. [130] In their work, ten equivalents of water were added as an additive to enhance the efficiency. Recently, our group also made some contributions to this area. Scheme 1.36: Selected examples of Iridium(III) _ catalyzed C-H bond amination. Besides rhodium catalysis, it is reasonable to investigate the catalytic ability of iridium, which is in group 9 and just below rhodium in the periodic table. [131] [123] [124] [125] They succeeded in the iridium-catalyzed intermolecular C-H amidation of arene assisted by various conventional directing groups, including benzamide 138, removable carbamate 163, ketoxime 117, pyridine 43, pyrazole 51, oxazoline 46, benzoxazole 175, isoquinoline 176, and acyl anilide 113. (Scheme 1.36) [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] Bolm and co _ workers extended this methodology in mechanochemistry AgOAc was used as the additive to enhance the efficacy. Recently, Lu and co-workers disclosed an iridium-catalyzed C-H amination of benzamides 138 by using alkyl azides 151 as the primary alkylamine source 130. A wide range of alkyl azides, including linear, branched, and cyclic alkyl azides were suitable coupling partners. Even biologically relevant molecules, such as amino acids, peptides, steroids, sugars, and thymidine derivatives could also be installed with high efficiency and complete chiral retention. [145] It was found that the CsOAc additive was vital for success and governed both the reactivity and the regioselectivity for this transformation. The group of Chang and Li group independently developed Ir(III)-catalyzed regioselective direct C7-amidation and amination of indolines 179 with various organoazides 149, such as sulfonyl, acyl, aryl, and alkyl azides 149-153 (Scheme 1.37). [146, 147] In Chang's work, easily removable N-protecting groups such as N-Boc or N-Cbz could readily be