Palladium Catalyzed C-H Bond Activation

The last decade has seen an explosive growth in the development of palladium catalyzed C—H bond activation reactions [81]. These have provided intriguing methods to couple the C—H bond of simple arenes with activated aryl halides, and 

An alternative strategy to the synthesis of nitrogen-containing heterocycies has been shown by Ackermann, with the coupling of simple anilines with 33 

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Methoxyquinoline is regioselectively oxidized at the methyl group by a chelate-directed palladium-catalyzed C-H bond activation <2004JA2300>. 8-Methylquinoline is selectively oxidized at the methyl position on treatment with palladium(ll) acetate followed by the oxidant phenyliodinium diacetate in acetic acid. The reaction proceeds via formation of a palladacycle (Scheme 4). Performing the reaction in methanol leads to isolation of 8-(methoxy-methyl)quinoline in 77% yield. 

Taking advantage of a palladium-catalyzed C-H bond activation, the a-chloroacetanilides 96 were transformed to the oxindoles 97. The reaction conditions applied tolerate a wide variety of functional groups <03JA12084>. 

In terms of miscellaneous reactions associated with aziridine synthesis, a ruthenium porphyrin catalyst was reported to facilitate a unique three-component coupling of nitroarenes with alkynes and a-diazo compounds to produce multifunctional aziridines (14OL1048). Pictured below is an intriguing palladium-catalyzed C-H bond activation/amination leading to the selective transformation of an aminolactone methyl group adjacent to an unprotected secondary amine into an aziridine (14NAT129). 

Carbocyclization of aromatic iodides, bicychc aUcenes, and benzynes involving a palladium-catalyzed C-H bond activation as a key step. 

The functionalization of iV-iminopyridium ylides with various aryl and heteroarylbromides using a palladium-catalyzed C-H bond activation strategy has been reported (eq 27). This... 

A wide range of sulfoxides 78, except for the one with a 2-substituted phenyl group, were converted to the corresponding dibenzothiophenes 80 in moderate to high yields. The authors proposed that sulfoxides 78 are first transformed to 2 -mercaptobiphenyl-2-ylcarbaldehydes 79 by a palladium catalyst. Then the palladium-catalyzed C—H bond activation/intramolecular S-arylation of aldehydes 79 affords dibenzothiophene 80. Indeed, they confirmed that biphenyl-2-ylthiol (81) was converted to dibenzothiophene (82) under the palladium catalysts (Scheme 23.31). 

Most directed aliphatic C-H activation processes underwent a five-membered-ring cyclometalated intermediate. However, the article described a palladium-catalyzed C-H bond activation mode which proceeds through a remarkable four-membered-ring cyclopalladation pathway (Scheme 2.15). 

Palladium-catalyzed oxidative allylic C-H functionalization provides attractive methods for the transformations of olefins, and their utility can be further enhanced by the development of more effective ways to use molecular oxygen (or air) to promote the catalytic cycle. The results outlined in this chapter summarize significant progress in the coupling reaction between terminal alkene and various types of nucleophiles. Further studies will be directed to explorations of the scope of nucleophilic reagents and olefins, and elucidation of the mechanisms of those reactions. Such studies will play an important role in the ongoing development of Pd-catalyzed C-H bond activations. 

Scheme 7.44 Directed palladium(ll)-catalyzed C—H bond activation.

A chelation-assisted mthenium-catalyzed arylation of aldehyde 99 was accomplished in combination with a palladium complex [47]. This cooperative catalysis [48] proved applicable to organostannanes and aryl iodides as arylating reagents (Scheme 9.35). The direct arylation proceeded most likely through ruthenium-catalyzed C—H bond activation, subsequent transmetallation to palladium, and reductive elimination from a palladium intermediate. 

A few recent examples of related C-C bond-forming reactions, all involving a palladium-catalyzed C-H activation step at arenes, will be mentioned. Salts are produced in these reactions, or acetic acid, as in the first example. Allylation of indoles at the 3-position was achieved by using palladium acetate, and bipyridine and allylic acetates as the reactants (Scheme 5) [19]. 

This review will cover recent advances in the palladium-catalyzed C-H activation of the indole and pyrrole nucleus, specifically for the formation of new C-C bonds via arylation and alkenylation. Most commonly, activation is achieved through... 

Keywords Palladium-catalyzed Allylic C-H bond activation Unactivated olefin 7t-allylpalladium Oxidative functionalization... 

Palladium Catalysts Yu s group has carried out systematic studies on Pd-catalyzed alkylations of aryl C—H bonds. Stille-type cross-coupling reactions have been developed by directed C—H activation (Equation 11.30) [68]. The reaction rate is enhanced by benzoquinone and microwave irradiation. Significantly, carboxylic acid functionality can be used as an efficient directing group for aryl C— H bond activation (Equation 11.31) [69]. The reaction conditions can be applied to the carboxylation of vinyl C— H bonds. The possible intermediacy of a palladacycle has been confirmed by NMR spectra and X-ray crystallography. 

The addition of an oxidizing reagent makes reactions catalytic with respect to palladium(II). Palladium compounds catalyze many other reactions invol-ving C-H bond activation. For example, benzaldehyde and benzoic acid can be produced by partial oxidation of toluene applying the fuel cell reaction in the gas phase using palladium black as the anode. The authors proposed a n-aliyl-benzyl-Pd"" complex as the reactive intermediate [16]. 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

In 2012, Yu, Houk, and eo-workers showed a detailed DFT calculation to understand reactivity and stereoselectivity in the Pd-catalyzed diastereoselec-tive C(sp )—H bond activation process. Characterization of the trinuclear palladium-alkyl complexes discloses a clear picture of the chiral induction model (Scheme 5.2). Computational investigation has revealed that the reactions with Pr- and Pu-substituted oxazolines involve different catalyst resting states before C—H bond activation and that the lower reactivity of an Pr-substituted oxazoline results from greater stability of its catalyst resting state. DFT calculation indicated that C—H bond activation most likely occurs at the monomeric Pd center and the most preferred transition state for C—H bond aetivation contains two sterically bulky Pu groups on the carboxylic acid, and the oxazoline moieties are oriented in anti-positions which leads to the major diastereomer. 

Palladium catalyzed C—H activation and its application to multi-bond forming reactions, including construction of heterocycles 13COC2001. InCl3-catalyzed one-pot organic synthesis 12T8683. 

For reviews on the Fujiwara-Moritani reaction, see (a) Fujiwara, Y. (2002) Palladium-promoted alkene-arene coupling via C—H activation, in Handbook of Organopalladium Chemistry in Organic Synthesis, Vol. 2 (eds E.-i. Negishi and A. de Meijere), John Wiley Sons, Inc., New York, pp. 2863-71 (b) Jia, C., Kitamura, T. and Fujiwara, Y. (2001) Catalytic functionalization of arenes and alkanes via C—H bond activation. Acc. Chem. Res., 34, 633-9 (c) Fujiwara, Y. and Jia, C. (2001) New developments in transition metal-catalyzed synthetic reactions viaC—H bond activation. PureAppl. Chem., 73,319-24 (d) Moritani, I. and Fujiwara, Y. (1973) Aromatic substitution of olefins by palladium salts. Synthesis, 524-33. 

Various methodologies for catalytic direct arylations via C—H bond activation employing transition metals other than palladium have been developed in recent years. In particular, rhodium- and ruthenium-based complexes have enabled the development of promising protocols for catalytic direct arylations. Whilst rhodium catalysts were found broadly applicable to the direct aryiation of both arenes, as well as heteroarenes, ruthenium-catalyzed chelation-assisted C—H bond function-ahzations could be used for the conversion of a variety of attractive organic electrophiles. In addition, inexpensive copper and iron salts have recently been shown as economically attractive alternatives to previously developed more expensive catalysts. Given the economically and environmentally benign features of selective C—H bond functionalizations, the development of further valuable protocols is expected in this rapidly evolving research area. 

Similar substituent effects have been determined in the reaction of complexes 10 to form palladacycles 11 (Scheme 11.3) [31]. The opposite process-the intramolecular palladium-catalyzed arylation of alkanes to form dihydrobenzofuranes-has also been examined [32]. For this transformation, a mechanism based on a C—H bond-activation process by the aryl-Pd(II) involving a three-center transition state was found to be more consistent with the experimental kinetic isotope effect (3.6 at 115 °C), as well as with density functional theory (DFT) calculations. 

A palladium-catalyzed methylation of 2-arylpyridines with tibutylperoxyde, and related peroxides, was recently developed [47]. This transformation also involves a C—H bond-activation step by a Pd(II)R complex, although no isotope effect was observed in an intramolecular competition experiment, which suggests that a radical mechanism might be involved. 

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