C —H bond functionalization

A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of IV-substitution with bulky groups directing to C-3. The oxidative alkenylation of (V-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the (V-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. 

The C-C bond-forming coupling of solvent molecules via sp2- and r/ -C-H bond functionalizations can be achieved using an iridium complex based on the TpMe2 ligand (hydridotris(3,5-dimethylpyrazolyl)borate) (Equation (64)).65... 

The arylation of common heteroarenes could be governed by the choice of conditions. Free (NH)-heteroarenes were C-arylated via selective catalytic C-H bond functionalizations. The key to these transformations was the use of MgO, which enabled the formation of a salt of the heteroarene, hence offering N-protection in situ (Equations (84) and (85)). a... 

A mechanism has been proposed for this, and related transformations, involving a chelation assisted C-H bond functionalization. Following hydride addition to the solvent, acetone, and a transmetallation reaction, reductive elimination yields the ketimine. Hydrolysis of the latter affords the ketone (Equation (131)).114 114a... 

In this review, the recent developments in catalytic functionalization of C-H bonds by iridium complexes will be emphasized. For more information on previous work and their details, there are excellent reviews published recently on C-H bond functionalization by transition metal complexes generally [1-9], as well as with an emphasis on iridium [11, 16]. 

Oxidative amination of carbamates, sulfamates, and sulfonamides has broad utility for the preparation of value-added heterocyclic structures. Both dimeric rhodium complexes and ruthenium porphyrins are effective catalysts for saturated C-H bond functionalization, affording products in high yields and with excellent chemo-, regio-, and diastereocontrol. Initial efforts to develop these methods into practical asymmetric processes give promise that such achievements will someday be realized. Alkene aziridina-tion using sulfamates and sulfonamides has witnessed dramatic improvement with the advent of protocols that obviate use of capricious iminoiodinanes. Complexes of rhodium, ruthenium, and copper all enjoy application in this context and will continue to evolve as both achiral and chiral catalysts for aziridine synthesis. The invention of new methods for the selective and efficient intermolecular amination of saturated C-H bonds still stands, however, as one of the great challenges. 

C-H functionalization, 10, 121 C-H intermolecular functionalization, 10, 122 C-H intramolecular functionalization, 10, 130 olefin functionalization, 10, 155 /)3-Carbon atoms, C-H bond functionalization activated alkyl groups intermolecularly, 10, 111 activated alkyl groups intramolecularly, 10, 114 alkanes and alkyl units, 10, 102 Carbon-based ligands, alkali metal chemistry, 2, 3 Carbon-based 77-ligands, in molybdenum carbonyls alkenes, 5, 433 alkynes, 5, 435 allenes, 5, 433... 

The 8//-thieno 2,3-/ indole 181 was prepared from 3-(2-nitrophenyl)thiophene 180 by a palladium-catalyzed regioselective C-H bond functionalization driven by CO as the stochiometric reductant. The compound 181 was obtained as a mixture of regioisomers in the ratio 93 7, determined by H NMR spectroscopic analysis of the crude reaction mixture. After flash chromatography, 181 was isolated as a major isomer in 81% yield [43] (Scheme 32). 

Godula, K. and Sames, D. (2006) C—H bond functionalization in complex organic synthesis. Science, 312, 67. 

The concept-guided development of selective new C-arylation methods for imidazoles via C-H bond functionalization has been reported <03JA5274, 03JA10580>. By judicious choice of the proper catalyst, 2-phenylimidazole 130 can be selectively arylated at the 4-position to imidazoles 131 (palladium catalyst in presence of magnesium oxide and triphenylphosphine) or at the 2 -position to produce imidazoles 132 (ruthenium catalyst in the presence of cesium carbonate). 

Selective C-arylation of free (AW)-purines via catalytic C-H bond functionalization has been developed <03JA5274>. Substitution at the 2 or 8 positions of 9-ethyladenine with a variety of side-chains was accomplished in order to obtain non-xanthine adenosine receptor antagonists... 

In the period covered by this edition, the hypothesis of a concerted process in the C-H insertion reaction has been challenged by a stepwise mechanism with groups both pro and contra (Scheme 1). A number of computational studies appeared applying different levels of theory on different model systems. A minireview covering selective alkane C-H bond functionalizations has also appeared <2004MI247>. 

Pyrazole was selectively C-arylated via catalytic C-H bond functionalization using iodobenzene and palladium(ii) acetate in the presence of triphenylphosphine and magnesium oxide to give 3(5)-phenyl-l//-pyrazole 213 (Equation 38) <2003JA5274>. 

Consider, for instance, the ionization of methane. Starting from a localized description of the neutral molecule, one can assume that the lowest state of the positive ion is obtained by removing one electron to one of the C—H bond functions, and construct in this way four possible functions of the form... 

Presumably, the oxidative cyclization of 1 commences with direct palladation at the orfAo-position, forming o-arylpalladium(II) complex 3 in a fashion analogous to a typical electrophilic aromatic substitution (this notion is useful in predicting the regiochemistry of oxidative cyclizations). The mechanism of the second formal C—H bond functionalization step is not fully elucidated, but may occur either via (a) an intramolecular carbopalladation reaction (migratory insertion) followed by czHft-P-hydride elimination from 4 (Path A) (b) by o-bond metathesis (through a four-centered transition state) followed by reductive elimination (Path B) (c) by electrophilic aromatic substitution followed by C—C bond-forming reductive elimination (PathC) [9]. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Copper is underutilized as a catalyst for C-H bond functionalization even though it was the first transition metal shown to promote carbon-hydrogen bond arylation. In 1941, Steinkopf, Leitsmann, and Hofmann showed that Ullmann reaction of 2-iodothiophene produces substantial amounts of tritiophene [88], This reaction necessarily involves one C-H bond arylation step. Subsequently, it has been shown that electron-deficient arenes such as polynitrobenzenes and pentafluorobenzene,... 

Pd-Catalyzed C-H Bond Functionalization on the Indole and Pyrrole Nucleus... 

As discussed previously, another major challenge relates to achieving selectivity in the C-H bond functionalization step. The prevalence of C-H bonds in organic molecules means that it is necessary to activate C-H bonds specifically, usually amongst similar C-H environments. In terms of reactions at Pd(II) centres, described above, there are four main factors used to control the regioselectivity of the C-H functionalization. 

The indole and pyrrole nucleus are common structural motifs in a range of natural products and medicinal agents (Fig. 1). Therefore, methods for their selective and efficient functionalization are important targets for chemical synthesis. The inherent reactivity of these heteroarenes has attracted widespread interest as ideal substrates for direct metal-catalyzed C-H bond functionalization reactions. However, related to their intrinsic reactivity is their sensitivity to harsh aerobic reaction conditions, and so methods to enable direct transformations on these heteroarenes must take this into account. 

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