Syntheses via C-H Bond Functionalizations

Lutz Ackermann, Ancmt R. Kapdi, Harish K. Potukuchi, and Sergei I. Kozhushkov 

A protocol for cross-dehydrogenative oxidative coupling of the 2-arylpyridine 4 with the cycloalkane 5 under ruthenium catalysis was elegantly developed by Li and 

Handbook of Green Chemistry Volume 7 Green Synthesis, First Edition. Edited by Chao-Jun Li. 

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Additionally, heterocyclic molecules are an important class of compound that is frequently encountered in the medicinal and pharmaceutical chemistry. And numerous efforts have been made to synthesize the core heterocycies in the recent years [2b, 5]. Carbonyiative reactions have been applied in the synthesis of heterocycies as well [2b]. Here we wish to discuss the main progresses in the carbonyiative synthesis of heterocycies via the C-H bond functionalization. To make... 

The rapid development of organocatalysis impels chemists to discover new synthetic methodologies. Many important transformations that could only be realized by transition metal catalysis can now be achieved via organocatalysis. In 2010, Kim and coworkers reported a novel C-H bond functionalization reaction via a tandem 1,5-hydride transfer/ring closure sequence. Based on the iminium-enamine cascade activation of catalyst 33, the fused tetrahydroquino-Unes 35 could be synthesized from substrates 34 with good stereoselectivity. This is the first example of an organocatalytic intramolecular redox reaction (Scheme 36.10) [16]. 

The syntheses of benzyl derivatives from benzylic C—H are well developed. Traditionally, multi-step syntheses had to be used. Furthermore, a stoichiometric amount of base was used and toxic halides were produced. To avoid such problems, various catalytic methods have been developed recently via direct functionalization of benzylic C—H bonds. More recently, our group has reported the FeCl2-catalyzed oxidative activation of benzylic C—H bonds followed by a cross-coupling reaction to form C—C bonds (Equation 11.1) [7]. The reactions selectively cleave benzylic C—H bonds and avoid further oxidation. The present methodology opens a window for iron-catalyzed C—H bond oxidation and C—C bond formation. 

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. 

C-H o-bond activation of hydrocarbons by transition metal complexes is of considerable importance in modern organometallic chemistry and catalytic chemistry by transition-metal complexes [1], because a functional group can be introduced into alkanes and aromatic compounds through C-H o-bond activation. For instance, Fujiwara and Moritani previously reported synthesis of styrene derivatives from benzene and alkene via C-H o-bond activation of benzene by palladium(ll) acetate [2]. Recently, Periana and his collaborators succeeded to activate the C-H o-bond of methane by the platinum(ll) complex in sulfuric acid to synthesize methanol [3], Both are good examples of the reaction including the C-H o-bond activation. 

Almost at the same time as the first report of the Kiindig group in 2011, Kagan and co-workers realized an asymmetric synthesis of chiral indoline scaffolds via Pd°/bisphosphine catalyzed C(sp )—H bond functionalization. They briefly investigated a number of chiral ligands (R,R)-L16 gave the cyclization product in best results (Scheme 5.35). They also employed this method to synthesize cyclohexyl fused indolines in promising yields (up to 97%) and enantioselectivity (up to 93% ee). 

In the second method, the alkoxyamine-ftmctionalized backbone is prepared by a chemical modification of a preformed polymer. Abbasian and Entezami prepared alkoxyamine-functionalized poly(vinyl chloride) (PVC) in a three-step procedure. PVC was first arylated with toluene by Friedel-Crafts acylation followed by a bromination step using N-bromosuccinimide. The bromine atom was finally reacted via nucleophilic substitution by the TEMPO hydro-xylamine anion. PVC-g-PS was finally obtained after TEMPO-mediated polymerization of styrene. A TEMPO-functionalized isotactic poly(l-butene) macroinitiator was synthesized by Jo et al. who used a rhodium-catalyzed activation of the alkane C-H bonds and subsequent transformations of the boronate ester group into an hydroxyl pendant group. This reactive moiety was then used to attach a TEMPO-based alkoxyamine bearing another hydroxy function by an ether linkage. A method to prepare PE-g-PS from a poly(ethylene-co-m,p--methylstyrene) obtained by metallocene-catalyzed polymerization was also reported. The macroalkoxya-mine was synthesized after bromination with N-bromosuccinimide followed by a nucleophilic reaction with the TEMPO hydroxylamine anion. 

Sultones are the internal esters of hydroxy sulfonic acids and are the sulfur analogs of lactones. Sultones are demanded scaffolds in medicinal chemistry research. Biological studies on sultones are mainly concerned with their toxicological, skin sensitization, and antiviral activities [20]. Sultones are synthetically useful heterocycles which can react with a variety of compounds to introduce the alkylsulfonic acid function and therefore used as sulfoalkylating agents [21]. There have been several new developments for the synthesis of sultones which have also been applied in the total synthesis of natural products. In recent years, the palladium-catalyzed direct arylation of several aromatics via a C-H bond activation using aryl halides has led to successes. An intramolecular version of this reaction has allowed the synthesis of several biaryls via the formation of five- to seven-membered rings. Thus, the sultones should be synthesized by C-H activation via two pathways (Scheme 4.14). 

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